ALBERT

Description:    Defects in membrane trafficking and degradation are hallmarks of most, and maybe all, neurodegenerative disorders. Such defects typically result in the accumulation of undegraded proteins due to aberrant endosomal sorting, lysosomal degradation, or autophagy. The genetic or environmental cause of a specific disease may directly affect these membrane trafficking processes. Alternatively, changes in intracellular sorting and degradation can occur as cellular responses of degenerating neurons to unrelated primary defects such as insoluble protein aggregates or other neurotoxic insults. Importantly, altered membrane trafficking may contribute to the pathogenesis or indeed protect the neuron. The observation of dramatic changes to membrane trafficking thus comes with the challenging need to distinguish pathological from protective alterations. Here, we will review our current knowledge about the protective and destructive roles of membrane trafficking in neuronal maintenance and degeneration. In particular, we will first focus on the question of what type of membrane trafficking keeps healthy neurons alive in the first place. Next, we will discuss what alterations of membrane trafficking are known to occur in Alzheimer’s disease and other tauopathies, Parkinson’s disease, polyQ diseases, peripheral neuropathies, and lysosomal storage disorders. Combining the maintenance and degeneration viewpoints may yield insight into how to distinguish when membrane trafficking functions protectively or contributes to degeneration. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-1201-4 Authors Dong Wang, Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA Chih-Chiang Chan, Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA Smita Cherry, Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA P. Robin Hiesinger, Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9040, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Hypermethylation of SOCS genes is associated with many human cancers, suggesting a role as tumor suppressors. As adaptor molecules for ubiquitin ligases, SOCS proteins modulate turnover of numerous target proteins. Few SOCS targets identified so far have a direct role in cell cycle progression; the mechanism by which SOCS regulate the cell cycle thus remains largely unknown. Here we show that SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and that SOCS1 associates specifically with Cdh1, triggering its degradation by the proteasome. Cells therefore show a G1/S transition defect, as well as a secondary blockade in mitosis and accumulation of cells in metaphase. SOCS1 expression correlated with a reduction in cyclin D/E levels and an increase in the tumor suppressor p19, as well as the CDK inhibitor p53, explaining the G1/S transition defect. As a result of Cdh1 degradation, SOCS1-expressing cells accumulated cyclin B1 and securin, as well as apparently inactive Cdc20, in mitosis. Levels of the late mitotic Cdh1 substrate Aurora A did not change. These observations comprise a hitherto unreported mechanism of SOCS1 tumor suppression, suggesting this molecule as a candidate for the design of new therapeutic strategies for human melanoma. Content Type Journal Article Category Research article Pages 1-14 DOI 10.1007/s00018-012-1145-8 Authors Verónica Parrillas, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Laura Martínez-Muñoz, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Borja L. Holgado, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Amit Kumar, PI3K Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, 28049 Madrid, Spain Graciela Cascio, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Pilar Lucas, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain José Miguel Rodríguez-Frade, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Marcos Malumbres, Cell Division and Cancer Group, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain Ana C. Carrera, PI3K Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, 28049 Madrid, Spain Karel HM van Wely, Genetic Instability Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, 28049 Madrid, Spain Mario Mellado, Chemokines Group, Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, Cantoblanco, 28049 Madrid, Spain Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The myosin isoform composition of the heart is dynamic in health and disease and has been shown to affect contractile velocity and force generation. While different mammalian species express different proportions of α and β myosin heavy chain, healthy human heart ventricles express these isoforms in a ratio of about 1:9 (α:β) while failing human ventricles express no detectable α-myosin. We report here fast-kinetic analysis of recombinant human α and β myosin heavy chain motor domains. This represents the first such analysis of any human muscle myosin motor and the first of α-myosin from any species. Our findings reveal substantial isoform differences in individual kinetic parameters, overall contractile character, and predicted cycle times. For these parameters, α-subfragment 1 (S1) is far more similar to adult fast skeletal muscle myosin isoforms than to the slow β isoform despite 91% sequence identity between the motor domains of α- and β-myosin. Among the features that differentiate α- from β-S1: the ATP hydrolysis step of α-S1 is ~ten-fold faster than β-S1, α-S1 exhibits ~five-fold weaker actin affinity than β-S1, and actin·α-S1 exhibits rapid ADP release, which is 〉ten-fold faster than ADP release for β-S1. Overall, the cycle times are ten-fold faster for α-S1 but the portion of time each myosin spends tightly bound to actin (the duty ratio) is similar. Sequence analysis points to regions that might underlie the basis for this finding. Content Type Journal Article Category Erratum Pages 1-17 DOI 10.1007/s00018-012-1111-5 Authors John C. Deacon, Department of Molecular, Cellular and Developmental Biology and Biofrontiers Institute, University of Colorado, MCDB, UCB 347, Boulder, CO 80309, USA Marieke J. Bloemink, School of Biosciences, University of Kent, Canterbury, CT2 7NJ UK Heresh Rezavandi, School of Biosciences, University of Kent, Canterbury, CT2 7NJ UK Michael A. Geeves, School of Biosciences, University of Kent, Canterbury, CT2 7NJ UK Leslie A. Leinwand, Department of Molecular, Cellular and Developmental Biology and Biofrontiers Institute, University of Colorado, MCDB, UCB 347, Boulder, CO 80309, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The T cell integrin receptor LFA-1 orchestrates adhesion between T cells and antigen-presenting cells (APCs), resulting in formation of a contact zone known as the immune synapse (IS) which is supported by the cytoskeleton. L-plastin is a leukocyte-specific actin bundling protein that rapidly redistributes to the immune synapse following T cell–APC engagement. We used single domain antibodies (nanobodies, derived from camelid heavy-chain only antibodies) directed against functional and structural modules of L-plastin to investigate its contribution to formation of an immune synapse between Raji cells and human peripheral blood mononuclear cells or Jurkat T cells. Nanobodies that interact either with the EF hands or the actin binding domains of L-plastin both trapped L-plastin in an inactive conformation, causing perturbation of IS formation, MTOC docking towards the plasma membrane, T cell proliferation and IL-2 secretion. Both nanobodies delayed Ser 5 phosphorylation of L-plastin which is required for enhanced bundling activity. Moreover, one nanobody delayed LFA-1 phosphorylation, reduced the association between LFA-1 and L-plastin and prevented LFA-1 enrichment at the IS. Our findings reveal subtle mechanistic details that are difficult to attain by conventional means and show that L-plastin contributes to immune synapse formation at distinct echelons. Content Type Journal Article Category Research article Pages 1-14 DOI 10.1007/s00018-012-1169-0 Authors Sarah De Clercq, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Olivier Zwaenepoel, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Evelien Martens, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Joël Vandekerckhove, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Aude Guillabert, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Jan Gettemans, Department of Medical Protein Research, VIB, 9000 Ghent, Belgium Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The yeast SUMO (small ubiquitin-like modifier) orthologue SMT3 was initially discovered in a genetic suppressors screen for the centromeric protein Mif2 (Meluh and Koshland in Mol Bio Cell 6:793–807, 1 ). Later, it turned out that the homologous mammalian proteins SUMO1 to SUMO4 are reversible protein modifiers that can form isopeptide bonds with lysine residues of respective target proteins (Mahajan et al. in Cell 88:97–107, 2 ). This was the discovery of a post-translational modification called sumoylation, which enzymatically resembles ubiquitination. However, very soon it became clear that SUMO attachments served a far more diverse role than ubiquitination. Meanwhile, numerous cellular processes are known to be subject to the impact of SUMO modification, including transcription, protein targeting, protein solubility, apoptosis or activity of various enzymes. In many instances, SUMO proteins create new protein interaction surfaces or block existing interaction domains (Geiss-Friedlander and Melchior in Nat Rev in Mol Cell Biol 8:947–956, 3 ). For the past few years, sumoylation attracted increasing attention as a versatile regulator of toxic protein properties in neurodegenerative diseases. In this review, we summarize the growing knowledge about the involvement of sumoylation in neurodegeneration, and discuss the underlying molecular principles affected by this multifaceted and intriguing post-translational modification. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-1158-3 Authors Petranka Krumova, Neuroscience, Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland Jochen H. Weishaupt, Neurology Department, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The vast majority of mammalian testes are located outside the body cavity for proper thermoregulation. Heat has an adverse effect on mammalian spermatogenesis and eventually leads to sub- or infertility. Recent studies have provided insights into the molecular response of male germ cells to high temperatures. Here, we review the effects of heat on male germ cells and discuss the mechanisms underlying germ cell loss and impairment. We also discuss the role of translational control in male germ cells as a potential protective mechanism against heat-induced germ cell apoptosis. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-1165-4 Authors Byunghyuk Kim, Department of Biological Sciences, Seoul National University, Seoul, 151-747 Korea Kyosun Park, Department of Biological Sciences, Seoul National University, Seoul, 151-747 Korea Kunsoo Rhee, Department of Biological Sciences, Seoul National University, Seoul, 151-747 Korea Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Reelin-Disabled-1 (Dab1) signaling has a well-established role in regulating neuronal migration during brain development. Binding of Reelin to its receptors induces Dab1 tyrosine phosphorylation. Tyrosine-phosphorylated Dab1 recruits a wide range of SH2 domain-containing proteins and activates multiple signaling cascades, resulting in cytoskeleton remodeling and precise neuronal positioning. In this review, we summarize recent progress in the Reelin-Dab1 signaling field. We focus on Dab1 alternative splicing as a mechanism for modulating the Reelin signal in developing brain. We suggest that correct positioning of neurons in the developing brain is at least partly controlled by alternatively-spliced Dab1 isoforms that differ in the number and type of tyrosine phosphorylation motifs that they contain. We propose a model whereby different subsets of SH2 domain-containing proteins are activated by different Dab1 isoforms, resulting in coordinated migration of neurons. Content Type Journal Article Category Review Pages 1-11 DOI 10.1007/s00018-012-1171-6 Authors Zhihua Gao, Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada Roseline Godbout, Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The insulin signaling pathway regulates whole-body glucose homeostasis by transducing extracellular signals from the insulin receptor (IR) to downstream intracellular targets, thus coordinating a multitude of biological functions. Dysregulation of IR or its signal transduction is associated with insulin resistance, which may culminate in type 2 diabetes. Following initial stimulation of IR, insulin signaling diverges into different pathways, activating multiple substrates that have roles in various metabolic and cellular processes. The integration of multiple pathways arising from IR activation continues to expand as new IR substrates are identified and characterized. Accordingly, our review will focus on roles for IR substrates as they pertain to three primary areas: metabolism/glucose uptake, mitogenesis/growth, and aging/longevity. While IR functions in a seemingly pleiotropic manner in many cell types, through these three main roles in fat and skeletal muscle cells, IR multi-tasks to regulate whole-body glucose homeostasis to impact healthspan and lifespan. Content Type Journal Article Category Review Pages 1-20 DOI 10.1007/s00018-012-1176-1 Authors Latha Ramalingam, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA Eunjin Oh, Department of Pediatrics, Herman B Wells Center, Indiana University School of Medicine, Indianapolis, IN, USA Debbie C. Thurmond, Departments of Pediatrics, Biochemistry and Molecular Biology, and Cellular and Integrative Physiology, Herman B Wells Center, Indiana University School of Medicine, 635 Barnhill Drive MS 2031, Indianapolis, IN 46202, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The schizophrenia susceptibility gene, Rgs4 , is one of the most intensively studied regulators of G-protein signaling members, well known to be fundamental in regulating neurotransmission. However, little is known about its role in the developing nervous system. We have isolated zebrafish rgs4 and shown that it is transcribed in the developing nervous system. Rgs4 knockdown did not affect neuron number and patterning but resulted in locomotion defects and aberrant development of axons. This was confirmed using a selective Rgs4 inhibitor, CCG-4986. Rgs4 knockdown also attenuated the level of phosphorylated-Akt1, and injection of constitutively-activated AKT1 rescued the motility defects and axonal phenotypes in the spinal cord but not in the hindbrain and trigeminal neurons. Our in vivo analysis reveals a novel role for Rgs4 in regulating axonogenesis during embryogenesis, which is mediated by another schizophrenia-associated gene, Akt1 , in a region-specific manner. Content Type Journal Article Category Research article Pages 1-16 DOI 10.1007/s00018-012-1178-z Authors Yi-Chuan Cheng, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Paul J. Scotting, Children’s Brain Tumour Research Centre, Centre for Genetics and Genomics, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH UK Li-Sung Hsu, Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, 40201 Taiwan Sheng-Jia Lin, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Hung-Yu Shih, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Fu-Yu Hsieh, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Hui-Lan Wu, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Chu-Li Tsao, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Chia-Jung Shen, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan, 33383 Taiwan Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Posttranslational modifications such as phosphorylation are universally acknowledged regulators of protein function. Recently we characterised a striated muscle-specific isoform of the formin FHOD3 that displays distinct subcellular targeting and protein half-life compared to its non-muscle counterpart and which is dependent on phosphorylation by CK2 (formerly casein kinase 2). We now show that the two isoforms of FHOD3 are already expressed in the vertebrate embryonic heart. Analysis of CK2 alpha knockout mice showed that phosphorylation by CK2 is also required for proper targeting of muscle FHOD3 to the myofibrils in embryonic cardiomyocytes in situ. The localisation of muscle FHOD3 in the sarcomere varies depending on the maturation state, being either broader or restricted to the Z -disc proper in the adult heart. Following myofibril disassembly, such as that in dedifferentiating adult rat cardiomyocytes in culture, the expression of non-muscle FHOD3 is up-regulated, which is reversed once the myofibrils are reassembled. The shift in expression levels of different isoforms is accompanied by an increased co-localisation with p62, which is involved in autophagy, and affects the half-life of FHOD3. Phosphorylation of three amino acids in the C-terminus of FHOD3 by ROCK1 is sufficient for activation, which results in increased actin filament synthesis in cardiomyocytes and also a broader localisation pattern of FHOD3 in the myofibrils. ROCK1 can directly phosphorylate FHOD3, and FHOD3 seems to be the downstream mediator of the exaggerated actin filament formation phenotype that is induced in cardiomyocytes upon the overexpression of constitutively active ROCK1. We conclude that the expression of the muscle FHOD3 isoform is characteristic of the healthy mature heart and that two distinct phosphorylation events are crucial to regulate the activity of this isoform in thin filament assembly and maintenance. Content Type Journal Article Category Research article Pages 1-16 DOI 10.1007/s00018-012-1154-7 Authors Thomas Iskratsch, Muscle Cell Biology Section, The Randall Division of Cell and Molecular Biophysics and The Cardiovascular Division, BHF Research Excellence Centre, King’s College London, New Hunt’s House, Guy’s Campus, London, SE1 1UL UK Susan Reijntjes, Institute of Medical Sciences, University of Aberdeen, Scotland, UK Joseph Dwyer, Muscle Cell Biology Section, The Randall Division of Cell and Molecular Biophysics and The Cardiovascular Division, BHF Research Excellence Centre, King’s College London, New Hunt’s House, Guy’s Campus, London, SE1 1UL UK Paul Toselli, Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA Irene R. Dégano, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA Isabel Dominguez, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA Elisabeth Ehler, Muscle Cell Biology Section, The Randall Division of Cell and Molecular Biophysics and The Cardiovascular Division, BHF Research Excellence Centre, King’s College London, New Hunt’s House, Guy’s Campus, London, SE1 1UL UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Trichomes, originating from epidermal cells, are present on nearly all terrestrial plants. They exist in diverse forms, are readily accessible, and serve as an excellent model system for analyzing the molecular mechanisms in plant cell differentiation, including cell fate choices, cell cycle control, and cell morphogenesis. In Arabidopsis , two regulatory models have been identified that function in parallel in trichome formation; the activator–inhibitor model and the activator–depletion model. Cotton fiber, a similar unicellular structure, is controlled by some functional homologues of Arabidopsis trichome-patterning genes. Multicellular trichomes, as in tobacco and tomato, may form through a distinct pathway from unicellular trichomes. Recent research has shown that cell cycle control participates in trichome formation. In this review, we summarize the molecular mechanisms involved in the formation of unicellular and multicellular trichomes, and discuss the integration of the cell cycle in its initiation and morphogenesis. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-1147-6 Authors Changxian Yang, The Key Laboratory of Horticultural Plant Biology, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070 China Zhibiao Ye, The Key Laboratory of Horticultural Plant Biology, Ministry of Education, Huazhong Agricultural University, Wuhan, 430070 China Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Haberlea rhodopensis is a resurrection plant with remarkable tolerance to desiccation. Haberlea exposed to drought stress, desiccation, and subsequent rehydration showed no signs of damage or severe oxidative stress compared to untreated control plants. Transcriptome analysis by next-generation sequencing revealed a drought-induced reprogramming, which redirected resources from growth towards cell protection. Repression of photosynthetic and growth-related genes during water deficiency was concomitant with induction of transcription factors (members of the NAC, NF-YA, MADS box, HSF, GRAS, and WRKY families) presumably acting as master switches of the genetic reprogramming, as well as with an upregulation of genes related to sugar metabolism, signaling, and genes encoding early light-inducible (ELIP), late embryogenesis abundant (LEA), and heat shock (HSP) proteins. At the same time, genes encoding other LEA, HSP, and stress protective proteins were constitutively expressed at high levels even in unstressed controls. Genes normally involved in tolerance to salinity, chilling, and pathogens were also highly induced, suggesting a possible cross-tolerance against a number of abiotic and biotic stress factors. A notable percentage of the genes highly regulated in dehydration and subsequent rehydration were novel, with no sequence homology to genes from other plant genomes. Additionally, an extensive antioxidant gene network was identified with several gene families possessing a greater number of antioxidant genes than most other species with sequenced genomes. Two of the transcripts most abundant during all conditions encoded catalases and five more catalases were induced in water-deficient samples. Using the pharmacological inhibitor 3-aminotriazole (AT) to compromise catalase activity resulted in increased sensitivity to desiccation. Metabolome analysis by GC or LC–MS revealed accumulation of sucrose, verbascose, spermidine, and γ-aminobutyric acid during drought, as well as particular secondary metabolites accumulating during rehydration. This observation, together with the complex antioxidant system and the constitutive expression of stress protective genes suggests that both constitutive and inducible mechanisms contribute to the extreme desiccation tolerance of H. rhodopensis . Content Type Journal Article Category Research article Pages 1-21 DOI 10.1007/s00018-012-1155-6 Authors Tsanko S. Gechev, Department of Plant Physiology and Plant Molecular Biology, University of Plovdiv, 24 Tsar Assen Str., Plovdiv, 4000 Bulgaria Maria Benina, Department of Plant Physiology and Plant Molecular Biology, University of Plovdiv, 24 Tsar Assen Str., Plovdiv, 4000 Bulgaria Toshihiro Obata, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Takayuki Tohge, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Neerakkal Sujeeth, Department of Plant Physiology and Plant Molecular Biology, University of Plovdiv, 24 Tsar Assen Str., Plovdiv, 4000 Bulgaria Ivan Minkov, Department of Plant Physiology and Plant Molecular Biology, University of Plovdiv, 24 Tsar Assen Str., Plovdiv, 4000 Bulgaria Jacques Hille, Molecular Biology of Plants, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands Mohamed-Ramzi Temanni, ServiceXS B.V., Plesmanlaan 1d, 2333 BZ Leiden, The Netherlands Andrew S. Marriott, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK Ed Bergström, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK Jane Thomas-Oates, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK Carla Antonio, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Bernd Mueller-Roeber, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Jos H. M. Schippers, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Alisdair R. Fernie, Max Planck Institute of Molecular Plant Physiology, Am Mühlenberg 1, 14476 Potsdam-Golm, Germany Valentina Toneva, Department of Plant Physiology and Plant Molecular Biology, University of Plovdiv, 24 Tsar Assen Str., Plovdiv, 4000 Bulgaria Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Since being discovered and intensively studied for over a decade, Smad ubiquitylation regulatory factor-1 (Smurf1) has been linked with several important biological pathways, including the bone morphogenetic protein pathway, the non-canonical Wnt pathway, and the mitogen-activated protein kinase pathway. Multiple functions of this ubiquitin ligase have been discovered in cell growth and morphogenesis, cell migration, cell polarity, and autophagy. Smurf1 is related to physiological manifestations in terms of age-dependent deficiency in bone formation and invasion of tumor cells. Smurf1-knockout mice have a significant phenotype in the skeletal system and considerable manifestations during embryonic development and neural outgrowth. In depth studying of Smurf1 will help us to understand the etiopathological mechanisms of related disorders. Here, we will summarize historical and recent studies on Smurf1, and discuss the E3 ligase-dependent and -independent functions of Smurf1. Moreover, intracellular regulations of Smurf1 and related physiological phenotypes will be described in this review. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1170-7 Authors Yu Cao, State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850 China Lingqiang Zhang, State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, 100850 China Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Hypoxic/ischemic injury remains the most dreaded cause of neurological disability and mortality. Despite the humbling experiences due to lack of promising therapy, our understanding of the complex cascades underlying the neuronal insult has led to advances in basic science research. One of the most noteworthy has been the effect of opioid receptors, especially the delta-opioid receptor (DOR), on hypoxic/ischemic neurons. Our recent studies, and those of others worldwide, present strong evidence that sheds light on DOR-mediated neuroprotection in the brain, especially in the cortex. The mechanisms of DOR neuroprotection are broadly categorized as: (1) stabilization of the ionic homeostasis, (2) inhibition of excitatory transmitter release, (3) attenuation of disrupted neuronal transmission, (4) increase in antioxidant capacity, (5) regulation of intracellular pathways—inhibition of apoptotic signals and activation of pro-survival signaling, (6) regulation of specific gene and protein expression, and (7) up-regulation of endogenous opioid release and/or DOR expression. Depending upon the severity and duration of hypoxic/ischemic insult, the release of endogenous opioids and DOR expression are regulated in response to the stress, and DOR signaling acts at multiple levels to confer neuronal tolerance to harmful insult. The phenomenon of DOR neuroprotection offers a potential clue for a promising target that may have significant clinical implications in our quest for neurotherapeutics. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1167-2 Authors Xiaozhou He, The Third Clinical College of Suzhou University, Changzhou, Jiangsu, China Harleen K. Sandhu, The Vivian L Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, 77030 TX, USA Yilin Yang, The Third Clinical College of Suzhou University, Changzhou, Jiangsu, China Fei Hua, The Third Clinical College of Suzhou University, Changzhou, Jiangsu, China Nathalee Belser, The Vivian L Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, 77030 TX, USA Dong H. Kim, The Vivian L Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, 77030 TX, USA Ying Xia, The Vivian L Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, 77030 TX, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Although essential for energy production and cell fate decisions, the mechanisms that govern protein homeostasis, or proteostasis, in mitochondria are only recently beginning to emerge. Fresh experimental evidence has uncovered a role of molecular chaperones of the heat shock protein 90 (Hsp90) family in overseeing the protein folding environment in mitochondria. Initially implicated in protection against cell death, there is now evidence that Hsp90-directed protein quality control in mitochondria connects to hosts of cellular homeostatic networks that become prominently exploited in human cancer. Content Type Journal Article Category Review Pages 1-10 DOI 10.1007/s00018-012-1177-0 Authors Dario C. Altieri, Prostate Cancer Discovery and Development Program, The Wistar Institute Cancer Center, 3601 Spruce Street, Philadelphia, PA 19104, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    In mammals, one of the two X chromosomes of female cells is inactivated for dosage compensation between the sexes. X chromosome inactivation is initiated in early embryos by the noncoding Xist RNA. Subsequent chromatin modifications on the inactive X chromosome (Xi) lead to a remarkable stability of gene repression in somatic cell lineages. In mice, reactivation of genes on the Xi accompanies the establishment of pluripotent cells of the female blastocyst and the development of primordial germ cells. Xi reactivation also occurs when pluripotency is established during the reprogramming of somatic cells to induced pluripotent stem cells. The mechanism of Xi reactivation has attracted increasing interest for studying changes in epigenetic patterns and for improving methods of cell reprogramming. Here, we review recent advances in the understanding of Xi reactivation during development and reprogramming and illustrate potential clinical applications. Content Type Journal Article Category Review Pages 1-19 DOI 10.1007/s00018-012-1174-3 Authors Tatsuya Ohhata, Wellcome Trust and MRC Stem Cell Institute, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR UK Anton Wutz, Wellcome Trust and MRC Stem Cell Institute, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Matricellular proteins interact with the extracellular matrix (ECM) and modulate cellular processes by binding to cell surface receptors and initiating intracellular signal transduction. Their association with the ECM and the ability of some members of this protein family to regulate cell motility have opened up new avenues of research to investigate their functions in normal and diseased cells. In this review, we summarize the research on CyrA, an ECM calmodulin-binding protein in Dictyostelium . CyrA is proteolytically cleaved into smaller EGF-like (EGFL) repeat containing cleavage products during development. The first EGFL repeat of CyrA binds to the cell surface and activates a novel signalling pathway that modulates cell motility in this model organism. The similarity of CyrA to the most well-characterized matricellular proteins in mammals allows it to be designated as the first matricellular protein identified in Dictyostelium . Content Type Journal Article Category Review Pages 1-9 DOI 10.1007/s00018-012-1068-4 Authors Robert J. Huber, Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON M5S 3G5, Canada Danton H. O’Day, Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON M5S 3G5, Canada Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The primary cilium protrudes from the cell surface and acts as a sensor for chemical and mechanical growth cues, with receptors for a number of growth factors (PDGFα, Hedgehog, Wnt, Notch) concentrated within the ciliary membrane. In normal tissues, the cilium assembles after cells exit mitosis and is resorbed as part of cell cycle re-entry. Although regulation of the cilium by cell cycle transitions has been appreciated for over 100 years, only recently have data emerged to indicate the cilium also exerts influence on the cell cycle. The resorption/protrusion cycle, regulated by proteins including Aurora-A, VHL, and GSK-3β, influences cell responsiveness to growth cues involving cilia-linked receptors; further, resorption liberates the ciliary basal body to differentiate into the centrosome, which performs discrete functions in S-, G2-, and M-phase. Besides these roles, the cilium provides a positional cue that regulates polarity of cell division, and thus directs cells towards fates of differentiation versus proliferation. In this review, we summarize the specific mechanisms mediating the cilia-cell cycle dialog. We then emphasize the examples of polycystic kidney disease (PKD), nephronopthisis (NPHP), and VHL-linked renal cysts as cases in which defects of ciliary function influence disease pathology, and may also condition response to treatment. Content Type Journal Article Category Review Pages 1-26 DOI 10.1007/s00018-012-1052-z Authors Junmin Pan, Protein Science Laboratory of the Ministry of Education, School of Life Sciences, Tsinghua University, Beijing, 100084 China Tamina Seeger-Nukpezah, Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA Erica A. Golemis, Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The gastrointestinal epithelium forms the boundary between the body and external environment. It effectively provides a selective permeable barrier that limits the permeation of luminal noxious molecules, such as pathogens, toxins, and antigens, while allowing the appropriate absorption of nutrients and water. This selective permeable barrier is achieved by intercellular tight junction (TJ) structures, which regulate paracellular permeability. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases. In this context, much effort has been taken to understand the roles of extracellular factors, including cytokines, pathogens, and food factors, for the regulation of the intestinal TJ barrier. Here, I discuss the regulation of the intestinal TJ barrier together with its implications for the pathogenesis of diseases. Content Type Journal Article Category Review Pages 1-29 DOI 10.1007/s00018-012-1070-x Authors Takuya Suzuki, Department of Biofunctional Science and Technology, Graduate School of Biosphere Science, Hiroshima University, 1-4-4, Kagamiyama, Higashi-Hiroshima, 739-8528 Japan Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Monoamine oxidases (MAOs) are flavoproteins of the outer mitochondrial membrane that catalyze the oxidative deamination of biogenic and xenobiotic amines. In mammals there are two isoforms (MAO-A and MAO-B) that can be distinguished on the basis of their substrate specificity and their sensitivity towards specific inhibitors. Both isoforms are expressed in most tissues, but their expression in the central nervous system and their ability to metabolize monoaminergic neurotransmitters have focused MAO research on the functionality of the mature brain. MAO activities have been related to neurodegenerative diseases as well as to neurological and psychiatric disorders. More recently evidence has been accumulating indicating that MAO isoforms are expressed not only in adult mammals, but also before birth, and that defective MAO expression induces developmental abnormalities in particular of the brain. This review is aimed at summarizing and critically evaluating the new findings on the developmental functions of MAO isoforms during embryogenesis. Content Type Journal Article Category Review Pages 1-32 DOI 10.1007/s00018-012-1065-7 Authors Chi Chiu Wang, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, Hong Kong Ellen Billett, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, NG11 8NS UK Astrid Borchert, Institute of Biochemistry, University Medicine Berlin-Charité, Oudenarder Str. 16, 13347 Berlin, Germany Hartmut Kuhn, Institute of Biochemistry, University Medicine Berlin-Charité, Oudenarder Str. 16, 13347 Berlin, Germany Christoph Ufer, Institute of Biochemistry, University Medicine Berlin-Charité, Oudenarder Str. 16, 13347 Berlin, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Understanding the peopling history of Europe is crucial to comprehend the origins of modern populations. Of course, the analysis of current genetic data offers several explanations about human migration patterns which occurred on this continent, but it fails to explain precisely the impact of each demographic event. In this context, direct access to the DNA of ancient specimens allows the overcoming of recent demographic phenomena, which probably highly modified the constitution of the current European gene pool. In recent years, several DNA studies have been successfully conducted from ancient human remains thanks to the improvement of molecular techniques. They have brought new fundamental information on the peopling of Europe and allowed us to refine our understanding of European prehistory. In this review, we will detail all the ancient DNA studies performed to date on ancient European DNA from the Middle Paleolithic to the beginning of the protohistoric period. Content Type Journal Article Category Review Pages 1-15 DOI 10.1007/s00018-012-1180-5 Authors Marie Lacan, Laboratoire AMIS, CNRS UMR 5288, 37 Allées Jules Guesde, 31073 Toulouse cedex 3, France Christine Keyser, Laboratoire AMIS, CNRS UMR 5288, 37 Allées Jules Guesde, 31073 Toulouse cedex 3, France Eric Crubézy, Laboratoire AMIS, CNRS UMR 5288, 37 Allées Jules Guesde, 31073 Toulouse cedex 3, France Bertrand Ludes, Laboratoire AMIS, CNRS UMR 5288, 37 Allées Jules Guesde, 31073 Toulouse cedex 3, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Most tumor cells exhibit a glycolytic phenotype. Thus, inhibition of glycolysis might be of therapeutic value in antitumor treatment. Among the agents that can suppress glycolysis is citrate, a member of the Krebs cycle and an inhibitor of phosphofructokinase. Here, we show that citrate can trigger cell death in multiple cancer cell lines. The lethal effect of citrate was found to be related to the activation of apical caspases-8 and -2, rather than to the inhibition of cellular energy metabolism. Hence, increasing concentrations of citrate induced characteristic manifestations of apoptosis, such as caspase-3 activation, and poly-ADP-ribose polymerase cleavage, as well as the release of cytochrome c . Apoptosis induction did not involve the receptor-mediated pathway, since the processing of caspase-8 was not attenuated in cells deficient in Fas-associated protein with Death Domain. We propose that the activation of apical caspases by citrate could be explained by its kosmotropic properties. Caspase-8 is activated by proximity-induced dimerization, which might be facilitated by citrate through the stabilization of intermolecular interactions between the proteins. Content Type Journal Article Category Research article Pages 1-9 DOI 10.1007/s00018-012-1166-3 Authors Björn Kruspig, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Azadeh Nilchian, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Sten Orrenius, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Boris Zhivotovsky, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Vladimir Gogvadze, Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    We investigated the effects of bone morphogenetic proteins (BMPs) in determining the positional identity of neurons generated in vitro from mouse embryonic stem cells (ESCs), an aspect that has been neglected thus far. Classical embryological studies in lower vertebrates indicate that BMPs inhibit the default fate of pluripotent embryonic cells, which is both neural and anterior. Moreover, mammalian ESCs generate neurons more efficiently when cultured in a minimal medium containing BMP inhibitors. In this paper, we show that mouse ESCs produce, secrete, and respond to BMPs during in vitro neural differentiation. After neuralization in a minimal medium, differentiated ESCs show a gene expression profile consistent with a midbrain identity, as evaluated by the analysis of a number of markers of anterior–posterior and dorsoventral identity. We found that BMPs endogenously produced during neural differentiation mainly act by inhibiting the expression of a telencephalic gene profile, which was revealed by the treatment with Noggin or with other BMP inhibitors. To better characterize the effect of BMPs on positional fate, we compared the global gene expression profiles of differentiated ESCs with those of embryonic forebrain, midbrain, and hindbrain. Both Noggin and retinoic acid (RA) support neuronal differentiation of ESCs, but they show different effects on their positional identity: whereas RA supports the typical gene expression profile of hindbrain neurons, Noggin induces a profile characteristic of dorsal telencephalic neurons. Our findings show that endogenously produced BMPs affect the positional identity of the neurons that ESCs spontaneously generate when differentiating in vitro in a minimal medium. The data also support the existence of an intrinsic program of neuronal differentiation with dorsal telencephalic identity. Our method of ESC neuralization allows for fast differentiation of neural cells via the same signals found during in vivo embryonic development and for the acquisition of cortical identity by the inhibition of BMP alone. Content Type Journal Article Category Research Article Pages 1-17 DOI 10.1007/s00018-012-1182-3 Authors Michele Bertacchi, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Luca Pandolfini, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Elisa Murenu, CIBIO, Università di Trento, Trento, Italy Alessandro Viegi, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Simona Capsoni, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Alessandro Cellerino, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Andrea Messina, CIBIO, Università di Trento, Trento, Italy Simona Casarosa, CIBIO, Università di Trento, Trento, Italy Federico Cremisi, Scuola Normale Superiore di Pisa, Piazza dei Cavalieri 7, 56100 Pisa, Italy Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1, IGF2BP2, IGF2BP3) belong to a conserved family of RNA-binding, oncofetal proteins. Several studies have shown that these proteins act in various important aspects of cell function, such as cell polarization, migration, morphology, metabolism, proliferation and differentiation. In this review, we discuss the IGF2BP family’s role in cancer biology and how this correlates with their proposed functions during embryogenesis. IGF2BPs are mainly expressed in the embryo, in contrast with comparatively lower or negotiable levels in adult tissues. IGF2BP1 and IGF2BP3 have been found to be re-expressed in several aggressive cancer types. Control of IGF2BPs’ expression is not well understood; however, let-7 microRNAs, β-catenin (CTNNB1) and MYC have been proposed to be involved in their regulation. In contrast to many other RNA-binding proteins, IGF2BPs are almost exclusively observed in the cytoplasm where they associate with target mRNAs in cytoplasmic ribonucleoprotein complexes (mRNPs). During development, IGF2BPs are required for proper nerve cell migration and morphological development, presumably involving the control of cytoskeletal remodeling and dynamics, respectively. Likewise, IGF2BPs modulate cell polarization, adhesion and migration in tumor-derived cells. Moreover, they are highly associated with cancer metastasis and the expression of oncogenic factors (KRAS, MYC and MDR1). However, a pro-metastatic role of IGF2BPs remains controversial due to the lack of ‘classical’ in vivo studies. Nonetheless, IGF2BPs could provide valuable targets in cancer treatment with many of their in vivo roles to be fully elucidated. Content Type Journal Article Category Review Pages 1-19 DOI 10.1007/s00018-012-1186-z Authors Jessica L. Bell, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Kristin Wächter, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Britta Mühleck, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Nikolaos Pazaitis, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Marcel Köhn, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Marcell Lederer, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Stefan Hüttelmaier, Section for Molecular Cell Biology, Institute of Molecular Medicine, Martin-Luther-University Halle, 06120 Halle, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Gram-negative bacteria can produce specific proteinaceous inhibitors to defend themselves against the lytic action of host lysozymes. So far, four different lysozyme inhibitor families have been identified. Here, we report the crystal structure of the Escherichia coli periplasmic lysozyme inhibitor of g-type lysozyme (PliG-Ec) in complex with Atlantic salmon g-type lysozyme (SalG) at a resolution of 0.95 Å, which is exceptionally high for a complex of two proteins. The structure reveals for the first time the mechanism of g-type lysozyme inhibition by the PliG family. The latter contains two specific conserved regions that are essential for its inhibitory activity. The inhibitory complex formation is based on a double ‘key-lock’ mechanism. The first key-lock element is formed by the insertion of two conserved PliG regions into the active site of the lysozyme. The second element is defined by a distinct pocket of PliG accommodating a lysozyme loop. Computational analysis indicates that this pocket represents a suitable site for small molecule binding, which opens an avenue for the development of novel antibacterial agents that suppress the inhibitory activity of PliG. Content Type Journal Article Category Research Article Pages 1-10 DOI 10.1007/s00018-012-1184-1 Authors S. Leysen, Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Herestraat 49 bus 822, 3000 Leuven, Belgium L. Vanderkelen, Laboratory of Food Microbiology, Leuven Food Science and Nutrition Research Centre (LFoRCe), Katholieke Universiteit Leuven, Kasteelpark Arenberg 22, 3001 Leuven, Belgium S. D. Weeks, Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Herestraat 49 bus 822, 3000 Leuven, Belgium C. W. Michiels, Laboratory of Food Microbiology, Leuven Food Science and Nutrition Research Centre (LFoRCe), Katholieke Universiteit Leuven, Kasteelpark Arenberg 22, 3001 Leuven, Belgium S. V. Strelkov, Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Herestraat 49 bus 822, 3000 Leuven, Belgium Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Cardiovascular disease is the foremost cause of morbidity and mortality in the Western world. Atherosclerosis followed by thrombosis (atherothrombosis) is the pathological process underlying most myocardial, cerebral, and peripheral vascular events. Atherothrombosis is a complex and heterogeneous inflammatory process that involves interactions between many cell types (including vascular smooth muscle cells, endothelial cells, macrophages, and platelets) and processes (including migration, proliferation, and activation). Despite a wealth of knowledge from many recent studies using knockout mouse and human genetic studies (GWAS and candidate approach) identifying genes and proteins directly involved in these processes, traditional cardiovascular risk factors (hyperlipidemia, hypertension, smoking, diabetes mellitus, sex, and age) remain the most useful predictor of disease. Eicosanoids (20 carbon polyunsaturated fatty acid derivatives of arachidonic acid and other essential fatty acids) are emerging as important regulators of cardiovascular disease processes. Drugs indirectly modulating these signals, including COX-1/COX-2 inhibitors, have proven to play major roles in the atherothrombotic process. However, the complexity of their roles and regulation by opposing eicosanoid signaling, have contributed to the lack of therapies directed at the eicosanoid receptors themselves. This is likely to change, as our understanding of the structure, signaling, and function of the eicosanoid receptors improves. Indeed, a major advance is emerging from the characterization of dysfunctional naturally occurring mutations of the eicosanoid receptors. In light of the proven and continuing importance of risk factors, we have elected to focus on the relationship between eicosanoids and cardiovascular risk factors. Content Type Journal Article Category Review Pages 1-20 DOI 10.1007/s00018-012-0982-9 Authors Scott Gleim, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 300 George Street #795H, New Haven, CT 06511, USA Jeremiah Stitham, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 300 George Street #795H, New Haven, CT 06511, USA Wai Ho Tang, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 300 George Street #795H, New Haven, CT 06511, USA Kathleen A. Martin, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 300 George Street #795H, New Haven, CT 06511, USA John Hwa, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, 300 George Street #795H, New Haven, CT 06511, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Age is an important risk for autoimmunity, and many autoimmune diseases preferentially occur in the second half of adulthood when immune competence has declined and thymic T cell generation has ceased. Many tolerance checkpoints have to fail for an autoimmune disease to develop, and several of those are susceptible to the immune aging process. Homeostatic T cell proliferation which is mainly responsible for T cell replenishment during adulthood can lead to the selection of T cells with increased affinity to self- or neoantigens and enhanced growth and survival properties. These cells can acquire a memory-like phenotype, in particular under lymphopenic conditions. Accumulation of end-differentiated effector T cells, either specific for self-antigen or for latent viruses, have a low activation threshold due to the expression of signaling and regulatory molecules and generate an inflammatory environment with their ability to be cytotoxic and to produce excessive amounts of cytokines and thereby inducing or amplifying autoimmune responses. Content Type Journal Article Category Multi-author review Pages 1-9 DOI 10.1007/s00018-012-0970-0 Authors Jörg J. Goronzy, Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, CCSR Building Room 2215, Mail Code 5166, 269 Campus Drive West, Stanford, CA 94305-5166, USA Cornelia M. Weyand, Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, CCSR Building Room 2215, Mail Code 5166, 269 Campus Drive West, Stanford, CA 94305-5166, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The human airway epithelium is a pseudostratified heterogenous layer comprised of ciliated, secretory, intermediate, and basal cells. As the stem/progenitor population of the airway epithelium, airway basal cells differentiate into ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. Transcriptome analysis of airway basal cells revealed high expression of vascular endothelial growth factor A (VEGFA), a gene not typically associated with the function of this cell type. Using cultures of primary human airway basal cells, we demonstrate that basal cells express all of the three major isoforms of VEGFA (121, 165 and 189) but lack functional expression of the classical VEGFA receptors VEGFR1 and VEGFR2. The VEGFA is actively secreted by basal cells and while it appears to have no direct autocrine function on basal cell growth and proliferation, it functions in a paracrine manner to activate MAPK signaling cascades in endothelium via VEGFR2-dependent signaling pathways. Using a cytokine- and serum-free co-culture system of primary human airway basal cells and human endothelial cells revealed that basal cell-secreted VEGFA activated endothelium to express mediators that, in turn, stimulate and support basal cell proliferation and growth. These data demonstrate novel VEGFA-mediated cross-talk between airway basal cells and endothelium, the purpose of which is to modulate endothelial activation and in turn stimulate and sustain basal cell growth. Content Type Journal Article Category Research Article Pages 1-15 DOI 10.1007/s00018-012-0922-8 Authors Giacomo Curradi, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Matthew S. Walters, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Bi-Sen Ding, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Shahin Rafii, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Neil R. Hackett, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Ronald G. Crystal, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The relatively homogenous clinical features and poor prognosis of chronic myelomonocytic leukemia (CMML) are associated with a molecular heterogeneity, with various mutations impacting several convergent pathways. Due to the restricted understanding of the mechanism involved in leukemogenesis, CMML still appears as a diagnostic and therapeutic undertaking, and poor prognosis of leukemia. Contrary to chronic myelogenous leukemia, BCR – ABL1 -positive, cytogenetic, and molecular abnormalities of CMML are not specific and not pathognomonic, confirming the different levels of heterogeneity of this disease. Various mutations can be associated with a common phenotype not distinct at the clinical level, further demonstrating that molecular probings are needed for choosing individual targeted therapies. Content Type Journal Article Category Review Pages 1-9 DOI 10.1007/s00018-012-0956-y Authors Jean-Noël Bastie, Faculté de Médecine, Inserm UMR 866, Université de Bourgogne, 7 bd Jeanne d’Arc, 21000 Dijon, France Romain Aucagne, Faculté de Médecine, Inserm UMR 866, Université de Bourgogne, 7 bd Jeanne d’Arc, 21000 Dijon, France Nathalie Droin, Inserm UMR 1009, IRCIV, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France Eric Solary, Inserm UMR 1009, IRCIV, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France Laurent Delva, Faculté de Médecine, Inserm UMR 866, Université de Bourgogne, 7 bd Jeanne d’Arc, 21000 Dijon, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The proteasome is a multi-catalytic protein complex whose primary function is the degradation of abnormal or foreign proteins. Upon exposure of cells to interferons (IFNs), the β1i/LMP2, β2i/MECL-1, and β5i/LMP7 subunits are induced and incorporated into newly synthesized immunoproteasomes (IP), which are thought to function solely as critical players in the optimization of the CD8 + T-cell response. However, the observation that IP are present in several non-immune tissues under normal conditions and/or following pathological events militates against the view that its role is limited to MHC class I presentation. In support of this concept, the recent use of genetic models deficient for β1i/LMP2, β2i/MECL-1, or β5i/LMP7 has uncovered unanticipated functions for IP in innate immunity and non-immune processes. Herein, we review recent data in an attempt to clarify the role of IP beyond MHC class I epitope presentation with emphasis on its involvement in the regulation of protein homeostasis, cell proliferation, and cytokine gene expression. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-0938-0 Authors Frédéric Ebstein, Institut für Biochemie, Charité-Universitätsmedizin Berlin Campus CVK, Oudenarderstr.16, 13347 Berlin, Germany Peter-Michael Kloetzel, Institut für Biochemie, Charité-Universitätsmedizin Berlin Campus CVK, Oudenarderstr.16, 13347 Berlin, Germany Elke Krüger, Institut für Biochemie, Charité-Universitätsmedizin Berlin Campus CVK, Oudenarderstr.16, 13347 Berlin, Germany Ulrike Seifert, Institut für Biochemie, Charité-Universitätsmedizin Berlin Campus CVK, Oudenarderstr.16, 13347 Berlin, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Metabolic engineering is the enabling science of development of efficient cell factories for the production of fuels, chemicals, pharmaceuticals, and food ingredients through microbial fermentations. The yeast Saccharomyces cerevisiae is a key cell factory already used for the production of a wide range of industrial products, and here we review ongoing work, particularly in industry, on using this organism for the production of butanol, which can be used as biofuel, and isoprenoids, which can find a wide range of applications including as pharmaceuticals and as biodiesel. We also look into how engineering of yeast can lead to improved uptake of sugars that are present in biomass hydrolyzates, and hereby allow for utilization of biomass as feedstock in the production of fuels and chemicals employing S. cerevisiae . Finally, we discuss the perspectives of how technologies from systems biology and synthetic biology can be used to advance metabolic engineering of yeast. Content Type Journal Article Category Review Pages 1-20 DOI 10.1007/s00018-012-0945-1 Authors Kuk-Ki Hong, Novo Nordisk Centre for Biosustainability, Department of Chemical and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden Jens Nielsen, Novo Nordisk Centre for Biosustainability, Department of Chemical and Biological Engineering, Chalmers University of Technology, 412 96 Gothenburg, Sweden Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Centrins are small, highly conserved members of the EF-hand superfamily of calcium-binding proteins that are found throughout eukaryotes. They play a major role in ensuring the duplication and appropriate functioning of the ciliary basal bodies in ciliated cells. They have also been localised to the centrosome, which is the major microtubule organising centre in animal somatic cells. We describe the identification, cloning and characterisation of centrins in multiple eukaryotic species. Although centrins have been implicated in centriole biogenesis, recent results have indicated that centrosome duplication can, in fact, occur in the absence of centrins. We discuss these data and the non-centrosomal functions that are emerging for the centrins. In particular, we discuss the involvement of centrins in nucleotide excision repair, a process that repairs the DNA lesions that are induced primarily by ultraviolet irradiation. We discuss how centrin may be involved in these diverse processes and contribute to nuclear and cytoplasmic events. Content Type Journal Article Category Review Pages 1-19 DOI 10.1007/s00018-012-0961-1 Authors Tiago J. Dantas, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, University Road, Galway, Ireland Owen M. Daly, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, University Road, Galway, Ireland Ciaran G. Morrison, Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, University Road, Galway, Ireland Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The pathobiology of pulmonary arterial hypertension (PAH) involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to an increase in pulmonary vascular resistance, right heart failure and death. Its etiology may be idiopathic, but PAH is also frequently associated with underlying conditions such as connective tissue diseases. During the past decade, more than welcome novel therapies have been developed and are in development, including those increasingly targeting the remodeling process. These therapeutic options modestly increase the patients’ long-term survival, now approaching 60% at 5 years. However, non-invasive tools for confirming PAH diagnosis, and assessing disease severity and response to therapy, are tragically lacking and would help to select the best treatment. After exclusion of other causes of pulmonary hypertension, a final diagnosis still relies on right heart catheterization, an invasive technique which cannot be repeated as often as an optimal follow-up might require. Similarly, other techniques and biomarkers used for assessing disease severity and response to treatment generally lack specificity and have significant limitations. In this review, imaging as well as current and future circulating biomarkers for diagnosis, prognosis, and follow-up are discussed. Content Type Journal Article Category Review Pages 1-27 DOI 10.1007/s00018-012-0950-4 Authors Marjorie Barrier, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Jolyane Meloche, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Maria Helena Jacob, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Audrey Courboulin, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Steeve Provencher, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Sébastien Bonnet, Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Ste-Foy, Québec, QC G1V 4G5, Canada Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Cell adhesion molecule 1 (CADM1), expressed by human lung mast cells (HLMCs), mediates their adhesion to airway smooth muscle (ASM), and contributes to ASM-dependent HLMC proliferation and survival. CADM1 is expressed in alternatively spliced isoforms, but those present in HLMCs and their function are not known. We cloned three functional and one cryptic non-functional isoform with alternative splicing between exons 7/11 and 1/2, respectively, from HLMCs and human MC lines (HMC-1 and LAD2). Differentiated HLMCs and LAD2 cells expressed the functional isoform SP4 containing exons 7/8/11 (~80% of clones), as well as SP1 (exons 7/8/9/11) and a novel SP6 (exons 7/8/9/10/11). In contrast, immature HMC-1 cells expressed only functional SP4. SP4 overexpression in HMC-1 cells and HLMCs augmented homotypic adhesion to a greater extent than SP1 in various conditions. In contrast, CADM1 downregulation abolished homotypic adhesion, indicating that CADM1 is the sole receptor mediating mast cell aggregation. CADM1-mediated adhesion was enhanced by the presence of cell survival factors. SP1 overexpression in HMC-1 cells compromised survival compared to SP4 overexpression or control. CADM1 downregulation resulted in reduced viability and decreased expression of the pro-survival protein Mcl-1 L , but not Blc-2 or Bcl-X L , and increased caspase-3/7 activity in both HMC-1 cells and HLMCs. This coincided with decreased basal Kit levels in HLMCs. In summary, human MCs express multiple CADM1 isoforms which exhibit differential regulation of survival and homotypic adhesion. The most highly expressed SP4 isoform is likely to contribute to MC aggregation and longevity in mastocytosis, and augment the pathophysiology of allergic diseases. Content Type Journal Article Category Research Article Pages 1-14 DOI 10.1007/s00018-012-0948-y Authors Elena P. Moiseeva, Department of Infection, Immunity and Inflammation, Institute for Lung Health, Clinical Sciences Wing, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP UK Mark L. Leyland, Department of Biochemistry, University of Leicester, Leicester, UK Peter Bradding, Department of Infection, Immunity and Inflammation, Institute for Lung Health, Clinical Sciences Wing, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    A disintegrin and metalloproteinase10 (ADAM10) has been implicated as a major sheddase responsible for the ectodomain shedding of a number of important surface molecules including the amyloid precursor protein and cadherins. Despite a well-documented role of ADAM10 in health and disease, little is known about the regulation of this protease. To address this issue we conducted a split-ubiquitin yeast two-hybrid screen to identify membrane proteins that interact with ADAM10. The yeast experiments and co-immunoprecipitation studies in mammalian cell lines revealed tetraspanin15 (TSPAN15) to specifically associate with ADAM10. Overexpression of TSPAN15 or RNAi-mediated knockdown of TSPAN15 led to significant changes in the maturation process and surface expression of ADAM10. Expression of an endoplasmic reticulum (ER) retention mutant of TSPAN15 demonstrated an interaction with ADAM10 already in the ER. Pulse-chase experiments confirmed that TSPAN15 accelerates the ER-exit of the ADAM10–TSPAN15 complex and stabilizes the active form of ADAM10 at the cell surface. Importantly, TSPAN15 also showed the ability to mediate the regulation of ADAM10 protease activity exemplified by an increased shedding of N-cadherin and the amyloid precursor protein. In conclusion, our data show that TSPAN15 is a central modulator of ADAM10-mediated ectodomain shedding. Therapeutic manipulation of its expression levels may be an additional approach to specifically regulate the activity of the amyloid precursor protein alpha-secretase ADAM10. Content Type Journal Article Category Research Article Pages 1-14 DOI 10.1007/s00018-012-0960-2 Authors Johannes Prox, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Michael Willenbrock, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Silvio Weber, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Tobias Lehmann, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Dirk Schmidt-Arras, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Ralf Schwanbeck, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Paul Saftig, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Michael Schwake, Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, 24098 Kiel, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Oxidative stress and low-grade inflammation are the hallmarks of the aging process and are even more enhanced in many age-related degenerative diseases. Mitochondrial dysfunction and oxidative stress can provoke and potentiate inflammatory responses, but the mechanism has remained elusive. Recent studies indicate that oxidative stress can induce the assembly of multiprotein inflammatory complexes called the inflammasomes. Nod-like receptor protein 3 (NLRP3) is the major immune sensor for cellular stress signals, e.g., reactive oxygen species, ceramides, and cathepsin B. NLRP3 activation triggers the caspase-1-mediated maturation of the precursors of IL-1β and IL-18 cytokines. During aging, the autophagic clearance of mitochondria declines and dysfunctional mitochondria provoke chronic oxidative stress, which disturbs the cellular redox balance. Moreover, increased NF-κB signaling observed during aging could potentiate the expression of NLRP3 and cytokine proforms enhancing the priming of NLRP3 inflammasomes. Recent studies have demonstrated that NLRP3 activation is associated with several age-related diseases, e.g., the metabolic syndrome. We will review here the emerging field of inflammasomes in the appearance of the proinflammatory phenotype during the aging process and in age-related diseases. Content Type Journal Article Category Review Pages 1-15 DOI 10.1007/s00018-012-0962-0 Authors Antero Salminen, Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Johanna Ojala, Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Kai Kaarniranta, Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Anu Kauppinen, Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Rapid signal propagation along vertebrate axons is facilitated by their insulation with myelin, a plasma membrane specialization of glial cells. The recent application of ‘omics’ approaches to the myelinating cells of the central nervous system, oligodendrocytes, revealed their mRNA signatures, enhanced our understanding of how myelination is regulated, and established that the protein composition of myelin is much more complex than previously thought. This review provides a meta-analysis of the 〉1,200 proteins thus far identified by mass spectrometry in biochemically purified central nervous system myelin. Contaminating proteins are surprisingly infrequent according to bioinformatic prediction of subcellular localization and comparison with the transcriptional profile of oligodendrocytes. The integration of datasets also allowed the subcategorization of the myelin proteome into functional groups comprising genes that are coregulated during oligodendroglial differentiation. An unexpectedly large number of myelin-related genes cause—when mutated in humans—hereditary diseases affecting the physiology of the white matter. Systematic approaches to oligodendrocytes and myelin thus provide valuable resources for the molecular dissection of developmental myelination, glia–axonal interactions, leukodystrophies, and demyelinating diseases. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-0958-9 Authors Patricia de Monasterio-Schrader, Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany Olaf Jahn, Proteomics Group, Max Planck Institute of Experimental Medicine, Göttingen, Germany Stefan Tenzer, Institute of Immunology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany Sven P. Wichert, Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany Julia Patzig, Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany Hauke B. Werner, Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Established views on the maintenance of immunological memory have been challenged recently by the description of memory plasma cells and memory T helper (Th) lymphocytes residing in the bone marrow (BM) in dedicated survival niches, resting in terms of proliferation and migration. While memory plasma cells are no longer reactive to antigen, memory Th lymphocytes are in a state of attentive rest, and can be reactivated fast and efficiently. Here, we discuss the signals controlling these resting states, which the memory lymphocytes receive from their microenvironment. Content Type Journal Article Category Multi-author review Pages 1-5 DOI 10.1007/s00018-012-0969-6 Authors Koji Tokoyoda, German Rheumatism Research Center Berlin, Chariteplatz 1, 10117 Berlin, Germany Andreas Radbruch, German Rheumatism Research Center Berlin, Chariteplatz 1, 10117 Berlin, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Tetraspanins regulate a variety of cellular functions. However, the general cellular mechanisms by which tetraspanins regulate these functions remain poorly understood. In this article we collected the observations that tetraspanins regulate the formation and/or development of various tubular structures of cell membrane. Because tetraspanins and their associated proteins (1) are localized at the tubular structures, such as the microvilli, adhesion zipper, foot processes, and penetration peg, and/or (2) regulate the morphogenesis of these membrane tubular structures, tetraspanins probably modulate various cellular functions through these membrane tubular structures. Some tetraspanins inhibit membrane tubule formation and/or extension, while others promote them. We predict that tetraspanins regulate the formation and/or development of various membrane tubular structures: (1) microvilli or nanovilli at the plasma membranes free of cell and matrix contacts, (2) membrane tubules at the plasma membrane of cell-matrix and cell-cell interfaces, and (3) membrane tubules at the intracellular membrane compartments. These different membrane tubular structures likely share a common morphogenetic mechanism that involves tetraspanins. Tetraspanins probably regulate the morphogenesis of membrane tubular structures by altering (1) the biophysical properties of the cell membrane such as curvature and/or (2) the membrane connections of cytoskeleton. Since membrane tubular structures are associated with cell functions such as adhesion, migration, and intercellular communication, in all of which tetraspanins are involved, the differential effects of tetraspanins on membrane tubular structures likely lead to the functional difference of tetraspanins. Content Type Journal Article Category Review Pages 1-10 DOI 10.1007/s00018-012-0954-0 Authors Xin A. Zhang, Department of Medicine, Vascular Biology and Cancer Centers, University of Tennessee Health Science Center, Cancer Research Building Room 220, 19 South Manassas Street, Memphis, TN 38163, USA Chao Huang, Department of Medicine, Vascular Biology and Cancer Centers, University of Tennessee Health Science Center, Cancer Research Building Room 220, 19 South Manassas Street, Memphis, TN 38163, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    MicroRNAs (miRNAs) are a family of small, non-coding RNAs that control gene expression at the post-transcriptional level by destabilizing and inhibiting translation of their target messenger RNAs. MiRNAs are involved in the regulation of a number of fundamental biological processes, and their dysregulation is thought to contribute to several disease processes. Emerging evidence suggests that miRNAs also play a critical role in protecting the heritable genome by contributing to the regulation of the DNA damage response. Consequently, much recent investigative effort has been directed towards an improved understanding of how miRNAs are regulated in response to DNA damage. In this review, we discuss the most recent findings regarding the regulation of miRNA expression and the functional roles of miRNAs in the DNA damage response. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-0959-8 Authors Cecil Han, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Guohui Wan, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Robert R. Langley, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Xinna Zhang, Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Xiongbin Lu, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Interkinetic nuclear migration (INM) is an oscillatory nuclear movement that is synchronized with the progression of the cell cycle. The efforts of several researchers, following the first report of INM in 1935, have revealed many of the molecular mechanisms of this fascinating phenomenon linking the timing of the cell cycle and nuclear positioning in tissue. Researchers are now faced with a more fundamental question: is INM important for tissue, particularly brain, development? In this review, I summarize the current understanding of the regulatory mechanisms governing INM, investigations involving several different tissues and species, and possible explanations for how nuclear movement affects cell-fate determination and tissue formation. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-0952-2 Authors Yoichi Kosodo, Department of Anatomy, Kawasaki Medical School, 577 Matsushima, Kurashiki, 701-0192 Japan Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The world of RNAs is much more complex than previously thought, and has rapidly emerged as one of the most actively researched topics in the life sciences. Recently, two findings in this field were reported and given special attention: promoter-associated RNAs (paRNAs), a novel class of RNAs with numerous potential functions; and promoter-targeted RNA-induced transcriptional gene regulation, a new regulatory mechanism to control transcription. In this review, we summarize the studies in these two areas, and outline the current understanding with respect to the potential biological functions of paRNAs, and the molecular mechanisms of promoter-targeted RNA-induced transcriptional gene silencing and activation. Additionally, we seek to integrate these two areas, as paRNAs may have potential biological links with promoter-targeted RNA-induced transcriptional gene regulation. Finally, we will discuss the significance of identifying paRNAs and the possible use of promoter-targeted RNAs in gene regulation and therapy. Content Type Journal Article Category Review Pages 1-10 DOI 10.1007/s00018-012-0953-1 Authors Bing-xue Yan, Icesnow Yanyan Bioscience Association, Beijing, 100094 China Jin-xia Ma, Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Barrier properties of tight junctions are determined by the claudin protein family. Many claudins seal this barrier, but others form paracellular channels. Among these, no claudins with general and clear-cut anion selectivity have yet been described, while for claudin-10a and claudin-4, only circumstantial or small anion selectivities have been shown. A claudin with unknown function and tissue distribution is claudin-17. We characterized claudin-17 by overexpression and knock-down in two renal cell lines. Overexpression in MDCK C7 cell layers caused a threefold increase in paracellular anion permeability and switched these cells from cation- to anion-selective. Knockdown in LLC-PK 1 cells indorsed the finding of claudin-17-based anion channels. Mutagenesis revealed that claudin-17 anion selectivity critically depends on a positive charge at position 65. Claudin-17 expression was found in two organs: marginal in brain but abundant in kidney, where expression was intense in proximal tubules and gradually decreased towards distal segments. As claudin-17 is predominantly expressed in proximal nephrons, which exhibit substantial, though molecularly not defined, paracellular chloride reabsorption, we suggest that claudin-17 has a unique physiological function in this process. In conclusion, claudin-17 forms channels within tight junctions with distinct anion preference. Content Type Journal Article Category Research Article Pages 1-14 DOI 10.1007/s00018-012-0949-x Authors Susanne M. Krug, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Dorothee Günzel, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Marcel P. Conrad, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Rita Rosenthal, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Anja Fromm, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Salah Amasheh, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Jörg D. Schulzke, Division of Nutritional Medicine, Department of Gastroenterology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Michael Fromm, Institute of Clinical Physiology, Campus Benjamin Franklin, Charité, Freie Universität and Humboldt Universität, Hindenburgdamm 30, 12203 Berlin, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    In wound healing and development, large epithelial sheets migrate collectively, in defined directions, and maintain tight cell–cell adhesion. This type of movement ensures an essential function of epithelia, a barrier, which is lost when cells lose connection and move in isolation. Unless wounded, epithelial sheets in cultures normally do not have overall directional migration. Cell migration is mostly studied when cells are in isolation and in the absence of mature cell–cell adhesion; the mechanisms of the migration of epithelial sheets are less well understood. We used small electric fields (EFs) as a directional cue to instigate and guide migration of epithelial sheets. Significantly, cells in monolayer migrated far more efficiently and directionally than cells in isolation or smaller cell clusters. We demonstrated for the first time the group size-dependent directional migratory response in several types of epithelial cells. Gap junctions made a minimal contribution to the directional collective migration. Breaking down calcium-dependent cell–cell adhesion significantly reduced directional sheet migration. Furthermore, E-cadherin blocking antibodies abolished migration of cell sheets. Traction force analysis revealed an important role of forces that cells in the leading rows exert on the substratum. With EF, the traction forces of the leading edge cells coordinated in directional re-orientation. Our study thus identifies a novel mechanism—E-cadherin dependence and coordinated traction forces of leading cells in collective directional migration of large epithelial sheets. Content Type Journal Article Category Research Article Pages 1-11 DOI 10.1007/s00018-012-0951-3 Authors Li Li, Department of Dermatology, School of Medicine, Institute for Regenerative Cures, University of California at Davis, Suite 1630, 2921 Stockton Blvd., Room 1617, Sacramento, CA 95817, USA Robert Hartley, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD UK Bjoern Reiss, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD UK Yaohui Sun, Department of Dermatology, School of Medicine, Institute for Regenerative Cures, University of California at Davis, Suite 1630, 2921 Stockton Blvd., Room 1617, Sacramento, CA 95817, USA Jin Pu, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD UK Dan Wu, Department of Physics and Astronomy, University of Manitoba, Winnipeg, MB R3T 2N2, Canada Francis Lin, Department of Physics and Astronomy, University of Manitoba, Winnipeg, MB R3T 2N2, Canada Trung Hoang, Department of Biomedical Engineering, University of California at Davis, Davis, CA 95616, USA Soichiro Yamada, Department of Biomedical Engineering, University of California at Davis, Davis, CA 95616, USA Jianxin Jiang, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 400042 China Min Zhao, Department of Dermatology, School of Medicine, Institute for Regenerative Cures, University of California at Davis, Suite 1630, 2921 Stockton Blvd., Room 1617, Sacramento, CA 95817, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Heart disease is one of the leading causes of death worldwide and the number of patients with the disease is likely to grow with the continual decline in health for most of the developed world. Heart transplantation is one of the only treatment options for heart failure due to an acute myocardial infarction, but limited donor supply and organ rejection limit its widespread use. Cellular cardiomyoplasty, or cellular implantation, combined with various tissue-engineering methods aims to regenerate functional heart tissue. This review highlights the numerous cell sources that have been used to regenerate the heart as well as cover the wide range of tissue-engineering strategies that have been devised to optimize the delivery of these cells. It will probably be a long time before an effective regenerative therapy can make a serious impact at the bedside. Content Type Journal Article Category Review Pages 1-22 DOI 10.1007/s00018-012-0942-4 Authors Andre Alcon, Yale University School of Medicine, Yale University, New Haven, CT, USA Esra Cagavi Bozkulak, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale Stem Cell Center, Yale School of Medicine, Yale University, 300 George Street, Suite 773A, New Haven, CT 06520, USA Yibing Qyang, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale Stem Cell Center, Yale School of Medicine, Yale University, 300 George Street, Suite 773A, New Haven, CT 06520, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Sex chromosome inactivation in male germ cells is a paradigm of epigenetic programming during sexual reproduction. Recent progress has revealed the underlying mechanisms of sex chromosome inactivation in male meiosis. The trigger of chromosome-wide silencing is activation of the DNA damage response (DDR) pathway, which is centered on the mediator of DNA damage checkpoint 1 (MDC1), a binding partner of phosphorylated histone H2AX (γH2AX). This DDR pathway shares features with the somatic DDR pathway recognizing DNA replication stress in the S phase. Additionally, it is likely to be distinct from the DDR pathway that recognizes meiosis-specific double-strand breaks. This review article extensively discusses the underlying mechanism of sex chromosome inactivation. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-0941-5 Authors Yosuke Ichijima, Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA Ho-Su Sin, Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA Satoshi H. Namekawa, Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Chromogranin A (CgA), a secretory protein expressed by many neuroendocrine cells, neurons, cardiomyocytes, and keratinocytes, is the precursor of various peptides that regulate the carbohydrate/lipid metabolism and the cardiovascular system. We have found that CgA, locally administered to injured mice, can accelerate keratinocyte proliferation and wound healing. This biological activity was abolished by the Asp 45 Glu mutation. CgA and its N-terminal fragments, but not the corresponding Asp 45 Glu mutants, could selectively recognize the αvβ6-integrin on keratinocytes (a cell-adhesion receptor that is up-regulated during wound healing) and regulate keratinocyte adhesion, proliferation, and migration. No binding was observed to other integrins such as αvβ3, αvβ5, αvβ8, α5β1, α1β1, α3β1, α6β4, α6β7 and α9β1. Structure–activity studies showed that the entire CgA 39–63 region is crucial for αvβ6 recognition ( K i  = 7 nM). This region contains an RGD site (residues CgA 43–45 ) followed by an amphipathic α-helix (residues CgA 47–63 ), both crucial for binding affinity and selectivity. These results suggest that the interaction of the RGD/α-helix motif of CgA with αvβ6 regulates keratinocyte physiology in wound healing. Content Type Journal Article Category Research Article Pages 1-13 DOI 10.1007/s00018-012-0955-z Authors Flavio Curnis, Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy Anna Maria Gasparri, Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy Renato Longhi, Istituto di Chimica del Riconoscimento Molecolare, CNR, 20131 Milan, Italy Barbara Colombo, Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy Silvia D’Alessio, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy Fabio Pastorino, Laboratory of Oncology, Experimental Therapy Unit, G. Gaslini Children’s Hospital, 16148 Genoa, Italy Mirco Ponzoni, Laboratory of Oncology, Experimental Therapy Unit, G. Gaslini Children’s Hospital, 16148 Genoa, Italy Angelo Corti, Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The cerebrospinal fluid (CSF) has attracted renewed interest as an active signaling milieu that regulates brain development, homeostasis, and disease. Advances in proteomics research have enabled an improved characterization of the CSF from development through adulthood, and key neurogenic signaling pathways that are transmitted via the CSF are now being elucidated. Due to its immediate contact with neural stem cells in the developing and adult brain, the CSF’s ability to swiftly distribute signals across vast distances in the central nervous system is opening avenues to novel and exciting therapeutic approaches. In this review, we will discuss the development of the choroid plexus-CSF system, and review the current literature on how the CSF actively regulates mammalian brain development, behavior, and responses to traumatic brain injury. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-0957-x Authors Mauro W. Zappaterra, Department of Physical Medicine and Rehabilitation, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA Maria K. Lehtinen, Department of Pathology, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    In addition to its central roles in protein quality control, regulation of cell cycle, intracellular signaling, DNA damage response and transcription regulation, the ubiquitin–proteasome system (UPS) plays specific roles in the nervous system, where it contributes to precise connectivity through development, and later assures functionality by regulating a wide spectrum of neuron-specific cellular processes. Aberrations in this system have been implicated in the etiology of neurodevelopmental and neurodegenerative diseases. In this review, we provide an updated view on the UPS and highlight recent findings concerning its role in normal and diseased nervous systems. We discuss the advantages of the model organism Caenorhabditis elegans as a tool to unravel the major unsolved questions concerning this biochemical pathway and its involvement in nervous system function and dysfunction, and expose the new possibilities, using state-of-the-art techniques, to assess UPS function using this model system. Content Type Journal Article Category Review Pages 1-25 DOI 10.1007/s00018-012-0946-0 Authors Márcio S. Baptista, Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal Carlos B. Duarte, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal Patrícia Maciel, Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    microRNAs (miRNAs) are small, stable RNA molecules that post-transcriptionally regulate gene expression in plants and animals by base pairing to partially complementary sequences on target mRNAs to inhibit protein synthesis. More than 250 miRNAs are reportedly expressed in the retina, and miRNA gene regulation has been shown to affect retinal development, function, and disease. Here we highlight recent advances in understanding the functional roles of vertebrate retinal miRNAs. Details are emerging about the physiological impact of specific miRNAs in the developing and mature retina, and we discuss a group of emerging technologies for studying miRNAs, which can be employed to yield a deeper understanding of retinal miRNA gene regulation. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-0976-7 Authors Thomas R. Sundermeier, Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-4965, USA Krzysztof Palczewski, Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-4965, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Homeostasis in the immune system encompasses the mechanisms governing maintenance of a functional and diverse pool of lymphocytes, thus guaranteeing immunity to pathogens while remaining self-tolerant. Antigen-naïve T cells rely on survival signals through contact with self-peptide-loaded major histocompatibility complex (MHC) molecules plus interleukin (IL)-7. Conversely, antigen-experienced (memory) T cells are typically MHC-independent and they survive and undergo periodic homeostatic proliferation through contact with both IL-7 and IL-15. Also, non-conventional γδ T cells rely on a mix of IL-7 and IL-15 for their homeostasis, whereas natural killer cells are mainly dependent on contact with IL-15. Homeostasis of CD4 + T regulatory cells is different in being chiefly regulated by contact with IL-2. Notably, increased levels of these cytokines cause expansion of responsive lymphocytes, such as found in lymphopenic hosts or following cytokine injection, whereas reduced cytokine levels cause a decline in cell numbers. Content Type Journal Article Category Multi-author review Pages 1-12 DOI 10.1007/s00018-012-0968-7 Authors Onur Boyman, Allergy Unit, Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland Carsten Krieg, Allergy Unit, Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zurich, Switzerland Dirk Homann, Departments of Pediatrics, Immunology and Microbiology, Barbara Davis Center, University of Colorado Denver, M20-3202D, 1775 Aurora Court, Aurora, CO 80010, USA Jonathan Sprent, Immunology Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The discovery of discontiguous tRNA genes triggered studies dissecting the process of tRNA splicing. As a result, we have gained detailed mechanistic knowledge on enzymatic removal of tRNA introns catalyzed by endonuclease and ligase proteins. In addition to the elucidation of tRNA processing, these studies facilitated the discovery of additional functions of RNA ligases such as RNA repair and non-conventional mRNA splicing events. Recently, the identification of a new type of RNA ligases in bacteria, archaea, and humans closed a long-standing gap in the field of tRNA processing. This review summarizes past and recent findings in the field of tRNA splicing with a focus on RNA ligation as it preferentially occurs in archaea and humans. In addition to providing an integrated view of the types and phyletic distribution of RNA ligase proteins known to date, this survey also aims at highlighting known and potential accessory biological functions of RNA ligases. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-0944-2 Authors Johannes Popow, Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohrgasse 3, 1030 Vienna, Austria Alexander Schleiffer, Bioinformatics Department, Research Institute of Molecular Pathology (IMP)–IMBA, Dr. Bohrgasse 7, 1030 Vienna, Austria Javier Martinez, Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr. Bohrgasse 3, 1030 Vienna, Austria Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The epidermis and its appendages, such as the hair follicle (HF), continually regenerate throughout postnatal mammalian life due to the activity of resident epithelial stem cells (SCs). The follicular SC niche, or the bulge, is composed of a heterogeneous population of self-renewing multipotent cells. Multiple intrinsic molecular mechanisms promote the transition of follicular SCs from quiescence to activation. In addition, numerous extrinsic cell types influence the activity and characteristics of bulge cells. Ultimately, the balance between these intrinsic and extrinsic mechanisms influences the function of bulge cells during homeostasis and tissue regeneration and likely contributes to skin tumorigenesis. Here, we review both the intrinsic and extrinsic factors that contribute to the skin SC niche. Content Type Journal Article Category Review Pages 1-10 DOI 10.1007/s00018-012-0943-3 Authors Jill Goldstein, Molecular Cell Biology, Genetics and Development Program, Yale University, 219 Prospect St., Box 208103, New Haven, CT 06520, USA Valerie Horsley, Department of Molecular, Cell and Developmental Biology, Yale University, 219 Prospect St., Box 208103, New Haven, CT 06520, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The non-coding microRNA (miRNA) is involved in the regulation of hepatitis C virus (HCV) infection and offers an alternative target for developing anti-HCV agent. In this study, we aim to identify novel cellular miRNAs that directly target the HCV genome with anti-HCV therapeutic potential. Bioinformatic analyses were performed to unveil liver-abundant miRNAs with predicted target sequences on HCV genome. Various cell-based systems confirmed that let-7b plays a negative role in HCV expression. In particular, let-7b suppressed HCV replicon activity and down-regulated HCV accumulation leading to reduced infectivity of HCVcc. Mutational analysis identified let-7b binding sites at the coding sequences of NS5B and 5′-UTR of HCV genome that were conserved among various HCV genotypes. We further demonstrated that the underlying mechanism for let-7b-mediated suppression of HCV RNA accumulation was not dependent on inhibition of HCV translation. Let-7b and IFNα-2a also elicited a synergistic inhibitory effect on HCV infection. Together, let-7b represents a novel cellular miRNA that targets the HCV genome and elicits anti-HCV activity. This study thereby sheds new insight into understanding the role of host miRNAs in HCV pathogenesis and to developing a potential anti-HCV therapeutic strategy. Content Type Journal Article Category Research Article Pages 1-13 DOI 10.1007/s00018-012-0940-6 Authors Ju-Chien Cheng, Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 404 Taiwan, ROC Yung-Ju Yeh, Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 404 Taiwan, ROC Ching-Ping Tseng, Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan, ROC Sheng-Da Hsu, Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, 300 Taiwan, ROC Yu-Ling Chang, Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, 404 Taiwan, ROC Naoya Sakamoto, Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan Hsien-Da Huang, Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, 300 Taiwan, ROC Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Microarray technology outgrew the detection of simple intermolecular interactions, as incubation of slides with living cells opened new vistas. Cell-based array technology permits simultaneous detection of several different cell surface molecules, allowing the complex characterization of cells with an amount of information that is hardly assessed by any other technique. Furthermore, binding of cells to printed antibodies or ligands may induce their activation, and consequently the outcome of these interactions, such as phosphorylation, gene expression, secretion of various products; differentiation, proliferation and apoptosis of the cells are also measurable on arrays. Moreover, since cells can be transfected with printed vectors, over- or under-expression of selected genes is also achievable simultaneously, creating a nice tool for assessing the function of a given gene. The enormously high-throughput cell-based microarray technology enables testing the effect of external stimuli on a scale that was earlier unthinkable. This review summarizes the possible applications of cell-based arrays. Content Type Journal Article Category Review Pages 1-9 DOI 10.1007/s00018-012-0947-z Authors Krisztián Papp, Immunology Research Group, Hungarian Academy of Sciences, MTA-ELTE, Pázmány P.s. 1/C, Budapest, 1117 Hungary Zoltán Szittner, Diagnosticum Ltd., Attila u. 126, Budapest, 1047 Hungary József Prechl, Immunology Research Group, Hungarian Academy of Sciences, MTA-ELTE, Pázmány P.s. 1/C, Budapest, 1117 Hungary Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Gap junction channels link cytoplasms of adjacent cells. Connexins, their constitutive proteins, are essential in cell homeostasis and are implicated in numerous physiological processes. Spermatogenesis is a sophisticated model of germ cell proliferation, differentiation, survival, and apoptosis, in which a connexin isotype, connexin 43, plays a crucial role as evidenced by genomic approaches based on gene deletion. The balance between cell proliferation/differentiation/apoptosis is a prerequisite for maintaining levels of spermatozoa essential for fertility and for limiting anarchic cell proliferation, a major risk of testis tumor. The present review highlights the emerging role of connexins in testis pathogenesis, focusing specifically on two intimately interconnected human testicular diseases (azoospermia with impaired spermatogenesis and testicular germ cell tumors), whose incidence increased during the last decades. This work proposes connexin 43 as a potential cancer diagnostic and prognostic marker, as well as a promising therapeutic target for testicular diseases. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-1121-3 Authors Daniel Chevallier, Department of Urology, Pasteur Hospital, Nice, France Diane Carette, UMR S775, University Paris Descartes, 45 rue des Saints Pères, Paris, 75006 France Dominique Segretain, UMR S775, University Paris Descartes, 45 rue des Saints Pères, Paris, 75006 France Jérome Gilleron, INSERM U 1065, Team 5 “Physiopathologic Control of Germ Cell Proliferation: Genomic and Non Genomic Mechanisms”, University Nice Sophia-Antipolis, C3M, 151 route Saint-Antoine de Ginestière BP 2 3194, Nice Cedex 3, 06204 France Georges Pointis, INSERM U 1065, Team 5 “Physiopathologic Control of Germ Cell Proliferation: Genomic and Non Genomic Mechanisms”, University Nice Sophia-Antipolis, C3M, 151 route Saint-Antoine de Ginestière BP 2 3194, Nice Cedex 3, 06204 France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Sarcomas are a heterogeneous group of tumors with mesenchymal origins. Sarcomas are broadly classified into bone and soft tissue sarcomas with over 50 subtypes. Despite recent advances in sarcoma classification and treatment strategies, the prognosis of some aggressive sarcoma types remains poor due to treatment infectiveness and development of drug resistance. A better understanding of sarcoma pathobiology will significantly increase the potential for the development of therapeutics and treatment strategies. Recently, expressions of microRNAs (miRNA), a class of small non-coding RNAs, have been found to be deregulated in many sarcomas and are implicated in sarcoma pathobiology. Comprehensive understanding of gene regulatory networks mediated by miRNAs in each sarcoma type and the conservation of some shared/conserved miRNA-gene networks could be potentially investigated in the prevention, diagnosis, prognosis and as multi-modal treatment options in these cancers. In this review, we will discuss the current knowledge of miRNA–gene regulatory networks in various sarcoma types and give a perspective of the complex multilayer miRNA-mediated gene regulation in sarcomas. Content Type Journal Article Category Multi-author review Pages 1-15 DOI 10.1007/s00018-012-1127-x Authors Subbaya Subramanian, Department of Surgery, University of Minnesota, 11-212 Moos Tower (Mail Code: MMC 195), 515 Delaware St, S.E, Minneapolis, MN 55455, USA Reena V. Kartha, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description: MicroRNA regulatory networks and human disease Content Type Journal Article Category Multi-author review Pages 1-3 DOI 10.1007/s00018-012-1123-1 Authors Yin-Yuan Mo, University of Mississippi Medical Center, Cancer Institute, Jackson, MS, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The molecular features that dominate the binding mode of agonists by a broadly tuned olfactory receptor are analyzed through a joint approach combining cell biology, calcium imaging, and molecular modeling. The odorant/receptor affinities, estimated through statistics accrued during molecular dynamics simulations, are in accordance with the experimental ranking. Although in many systems receptors recognize their target through a network of oriented interactions, such as H-bonding, the binding by broadly tuned olfactory receptors is dominated by non-polar terms. We show how such a feature allows chemicals belonging to different chemical families to similarly activate the receptors through compensations of interactions within the binding site. Content Type Journal Article Category Research article Pages 1-9 DOI 10.1007/s00018-012-1116-0 Authors Landry Charlier, Institut de Chimie de Nice, UMR CNRS, Université de Nice Sophia Antipolis 7272, 06108 Nice Cedex 2, France Jérémie Topin, Institut de Chimie de Nice, UMR CNRS, Université de Nice Sophia Antipolis 7272, 06108 Nice Cedex 2, France Catherine Ronin, Laboratoire de Neuroglycobiologie, GLM, CNRS, 31 Ch. J. Aiguier, 13402 Marseille, France Soo-Kyung Kim, Materials and Process Simulation Center (MC139-74), California Institute of Technology, 1200 E. California Blvd., Pasadena, CA 91125, USA William A. Goddard III, Materials and Process Simulation Center (MC139-74), California Institute of Technology, 1200 E. California Blvd., Pasadena, CA 91125, USA Roman Efremov, Laboratory of Biomolecular Modeling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, 117997 Moscow, Russia Jérôme Golebiowski, Institut de Chimie de Nice, UMR CNRS, Université de Nice Sophia Antipolis 7272, 06108 Nice Cedex 2, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Cardiac hypertrophy is an adaptive enlargement of the myocardium in response to altered stress or injury. The cellular responses of cardiomyocytes and non-cardiomyocytes to various signaling pathways should be tightly and delicately regulated to maintain cardiac homeostasis and prevent pathological cardiac hypertrophy. MicroRNAs (miRNAs) are endogenous, single-stranded, short non-coding RNAs that act as regulators of gene expression by promoting the degradation or inhibiting the translation of target mRNAs. Recent studies have revealed expression signatures of miRNAs associated with pathological cardiac hypertrophy and heart failure in humans and mouse models of heart diseases. Increasing evidence indicates that dysregulation of specific miRNAs could alter the cellular responses of cardiomyocytes and non-cardiomyocytes to specific signaling upon the pathological hemodynamic overload, leading to cardiac hypertrophy and heart failure. This review summarizes the cell-autonomous functions of cardiomyocyte miRNAs regulated by different pathways and the roles of non-cardiomyocyte miRNAs in cardiac hypertrophy. The therapeutic effects of a number of miRNAs in heart diseases are also discussed. Content Type Journal Article Category Multi-author review Pages 1-10 DOI 10.1007/s00018-012-1126-y Authors Jian Wang, State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, 100071 Beijing, China Xiao Yang, State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, 20 Dongdajie, 100071 Beijing, China Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Pentameric ligand-gated ion channel (pLGIC) receptors exhibit desensitization, the progressive reduction in ionic flux in the prolonged presence of agonist. Despite its pathophysiological importance and the fact that it was first described over half a century ago, surprisingly little is known about the structural basis of desensitization in this receptor family. Here, we explain how desensitization is defined using functional criteria. We then review recent progress into reconciling the structural and functional basis of this phenomenon. The extracellular–transmembrane domain interface is a key locus. Activation is well known to involve conformational changes at this interface, and several lines of evidence suggest that desensitization involves a distinct conformational change here that is incompatible with activation. However, major questions remain unresolved, including the structural basis of the desensitization-induced agonist affinity increase and the mechanism of pore closure during desensitization. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1133-z Authors Angelo Keramidas, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia Joseph W. Lynch, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Tubulin cofactors (TBCs) participate in the folding, dimerization, and dissociation pathways of the tubulin dimer. Among them, TBCB and TBCE are two CAP-Gly domain-containing proteins that together efficiently interact with and dissociate the tubulin dimer. In the study reported here we showed that TBCB localizes at spindle and midzone microtubules during mitosis. Furthermore, the motif DEI/M-COO − present in TBCB, which is similar to the EEY/F-COO − element characteristic of EB proteins, CLIP-170, and α-tubulin, is required for TBCE–TBCB heterodimer formation and thus for tubulin dimer dissociation. This motif is responsible for TBCB autoinhibition, and our analysis suggests that TBCB is a monomer in solution. Mutants of TBCB lacking this motif are derepressed and induce microtubule depolymerization through an interaction with EB1 associated with microtubule tips. TBCB is also able to bind to the chaperonin complex CCT containing α-tubulin, suggesting that it could escort tubulin to facilitate its folding and dimerization, recycling or degradation. Content Type Journal Article Category Research article Pages 1-15 DOI 10.1007/s00018-012-1114-2 Authors Gerardo Carranza, Departamento de Biología Molecular, Facultad de Medicina, IFIMAV-Universidad de Cantabria, 39011 Santander, Spain Raquel Castaño, Departamento de Biología Molecular, Facultad de Medicina, IFIMAV-Universidad de Cantabria, 39011 Santander, Spain Mónica L. Fanarraga, Departamento de Biología Molecular, Facultad de Medicina, IFIMAV-Universidad de Cantabria, 39011 Santander, Spain Juan Carlos Villegas, Departamento de Anatomía y Biología Celular, Facultad de Medicina, IFIMAV-Universidad de Cantabria, 39011 Santander, Spain João Gonçalves, Centro de Química eBioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisbon, Portugal Helena Soares, Centro de Química eBioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisbon, Portugal Jesus Avila, Centro de Biología Molecular (CSIC-UAM), Universidad Autónoma de Madrid, 28049 Cantoblanco, Madrid, Spain Marco Marenchino, Spectroscopy and NMR Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Melchor Fdez. Almagro 3, 28029 Madrid, Spain Ramón Campos-Olivas, Spectroscopy and NMR Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Melchor Fdez. Almagro 3, 28029 Madrid, Spain Guillermo Montoya, Macromolecular Crystallography Group, Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Melchor Fdez. Almagro 3, 28029 Madrid, Spain Juan Carlos Zabala, Departamento de Biología Molecular, Facultad de Medicina, IFIMAV-Universidad de Cantabria, 39011 Santander, Spain Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Tumor cell migration is essential for invasion and dissemination from primary solid tumors and for the establishment of lethal secondary metastases at distant organs. In vivo and in vitro models enabled identification of different factors in the tumor microenvironment that regulate tumor progression and metastasis. However, the mechanisms by which tumor cells integrate these chemical and mechanical signals from multiple sources to navigate the complex microenvironment remain poorly understood. In this review, we discuss the factors that influence tumor cell migration with a focus on the migration of transformed carcinoma cells. We provide an overview of the experimental and computational methods that allow the investigation of tumor cell migration, and we highlight the benefits and shortcomings of the various assays. We emphasize that the chemical and mechanical stimulus paradigms are not independent and that crosstalk between them motivates the development of new assays capable of applying multiple, simultaneous stimuli and imaging the cellular migratory response in real-time. These next-generation assays will more closely mimic the in vivo microenvironment to provide new insights into tumor progression, inform techniques to control tumor cell migration, and render cancer more treatable. Content Type Journal Article Category Review Pages 1-22 DOI 10.1007/s00018-012-1115-1 Authors William J. Polacheck, Department of Mechanical Engineering, MIT, 77 Massachusetts Ave. Room NE47-315, Cambridge, MA 02139, USA Ioannis K. Zervantonakis, Department of Mechanical Engineering, MIT, 77 Massachusetts Ave. Room NE47-319, Cambridge, MA 02139, USA Roger D. Kamm, Departments of Mechanical Engineering and Biological Engineering, MIT, 77 Massachusetts Ave. Room NE47-321, Cambridge, MA 02139, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The emerging role of microRNAs (miRNAs) in the epigenetic regulation of many cellular processes has become recognized in both basic research and translational medicine as an important way that gene expression can be fine-tuned. Breast cancer is the most frequent cancer in women, with about one million new cases diagnosed each year worldwide. Starting with the early work of miRNA profiling, more effort has now been put on functions of miRNAs in normal mammary stem cells, breast cancer initiating cells and metastatic cells, and therapy-resistant cancer cells. Future translational studies may focus on identifying miRNA signatures as cancer biomarkers and developing miRNA-based targeted therapeutics. Content Type Journal Article Category Multi-author review Pages 1-13 DOI 10.1007/s00018-012-1128-9 Authors Huiping Liu, The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Integrin-mediated cytoskeletal tension supports growth-factor-induced proliferation, and disruption of the actin cytoskeleton in growth factor-stimulated cells prevents the re-expression of cyclin D and cell cycle re-entry from quiescence. In contrast to cells that enter the cell cycle from G0, cycling cells continuously express cyclin D, and are subject to major cell shape changes during the cell cycle. Here, we investigated the cell cycle requirements for cytoskeletal tension and cell spreading in cycling mammalian cells that enter G1-phase from mitosis. Disruption of the actin cytoskeleton at progressive time-points in G1-phase induced cell rounding, FA disassembly, and attenuated both integrin signaling and growth factor-induced p44/p42 mitogen-activated protein kinase activation. Although cyclin D expression was reduced, the expression of cyclin A and entry into S-phase were not affected. Moreover, expression of cyclin B1, progression through G2- and M-phase, and commitment to a new cell cycle occurred normally. In contrast, cell cycle progression was strongly prevented by inhibition of MAPK activity in G1-phase, whereas cell spreading, cytoskeletal organization, and integrin signaling were not impaired. MAPK inhibition also prevented cytoskeleton-independent cell cycle progression. Thus, these results uncouple the requirements for cell spreading and cytoskeletal organization from MAPK signaling, and show that cycling mammalian cells can proliferate independently of actin stress fibers, focal adhesions, or cell spreading, as long as a threshold level of MAPK activity is sustained. Content Type Journal Article Category Research Article Pages 1-15 DOI 10.1007/s00018-012-1130-2 Authors Coert Margadant, Department of Cell Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands Lobke Cremers, Department of Cell Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands Arnoud Sonnenberg, Department of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands Johannes Boonstra, Department of Cell Biology, Faculty of Sciences, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The efficient transport of blood and lymph relies on competent intraluminal valves that ensure unidirectional fluid flow through the vessels. In the lymphatic vessels, lack of luminal valves causes reflux of lymph and can lead to lymphedema, while dysfunction of venous valves is associated with venous hypertension, varicose veins, and thrombosis that can lead to edema and ulcerations. Despite their clinical importance, the mechanisms that regulate valve formation are poorly understood and have only recently begun to be characterized. Here, we discuss new findings regarding the development of venous and lymphatic valves that indicate the involvement of common molecular mechanisms in regulating valve formation in different vascular beds. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-1110-6 Authors Eleni Bazigou, Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3LY UK Taija Makinen, Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3LY UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin −/− mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes. Content Type Journal Article Category Research Article Pages 1-25 DOI 10.1007/s00018-012-1106-2 Authors Tamara Jefferson, Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany Ulrich auf dem Keller, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology Zurich, ETH Hoenggerberg, HPM D24, Zurich, Switzerland Caroline Bellac, Departments of Oral Biological and Medical Sciences and Biochemistry and Molecular Biology, Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada Verena V. Metz, Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany Claudia Broder, Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany Jana Hedrich, Institute of Physiology and Pathophysiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany Anke Ohler, Cell and Matrix Biology, Johannes Gutenberg University, Mainz, Germany Wladislaw Maier, Institute of Pathobiochemistry, University Medical Center, Johannes Gutenberg-University, Mainz, Germany Viktor Magdolen, Clinical Research Unit, Department of Obstetrics and Gynecology, Technical University of Munich, Munich, Germany Erwin Sterchi, Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland Judith S. Bond, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA Arumugam Jayakumar, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, The University of Texas, Houston, TX, USA Heiko Traupe, Department of Dermatology, University Hospital Münster, Münster, Germany Athena Chalaris, Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany Stefan Rose-John, Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany Claus U. Pietrzik, Institute of Pathobiochemistry, University Medical Center, Johannes Gutenberg-University, Mainz, Germany Rolf Postina, Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University, Mainz, Germany Christopher M. Overall, Departments of Oral Biological and Medical Sciences and Biochemistry and Molecular Biology, Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada Christoph Becker-Pauly, Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1β has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1β upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K + , and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL-1 signaling pathway as the perspective target for the therapy of prion disease. Content Type Journal Article Category Research article Pages 1-14 DOI 10.1007/s00018-012-1140-0 Authors Iva Hafner-Bratkovič, Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia Mojca Benčina, Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia Katherine A. Fitzgerald, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, 55 Lake Avenue North, 01605 Worcester, MA, USA Douglas Golenbock, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, 55 Lake Avenue North, 01605 Worcester, MA, USA Roman Jerala, Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Somatic cell reprogramming consists of the induction of a complex sequence of events that results in the modification of the developmental state of the cell. It is now routinely possible to reprogram fully differentiated cells back to pluripotent cells, and to transdifferentiate cells of a given type in cells of a totally different lineage origin. However, whether there are key initiating factors that are distinct from those that control stem-cell renewal and that can initiate the reprogramming process remains unknown. In contrast, what is clear is that, by modifying the epigenetic status of a cell, its reprogramming can be initiated. Here, we review the current literature that shows how the plasticity of a cell can be modulated by modifying its epigenetic status, and we discuss how epigenetic barriers can be removed, to induce an efficient reprogramming process. Content Type Journal Article Category Review Pages 1-12 DOI 10.1007/s00018-012-1137-8 Authors Frederic Lluis, Centre for Genomic Regulation (CRG) and UPF, Dr. Aiguader, 88, 08003 Barcelona, Spain Maria Pia Cosma, Centre for Genomic Regulation (CRG) and UPF, Dr. Aiguader, 88, 08003 Barcelona, Spain Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The double-stranded RNA binding domain (dsRBD) is a small protein domain of 65–70 amino acids adopting an αβββα fold, whose central property is to bind to double-stranded RNA (dsRNA). This domain is present in proteins implicated in many aspects of cellular life, including antiviral response, RNA editing, RNA processing, RNA transport and, last but not least, RNA silencing. Even though proteins containing dsRBDs can bind to very specific dsRNA targets in vivo, the binding of dsRBDs to dsRNA is commonly believed to be shape-dependent rather than sequence-specific. Interestingly, recent structural information on dsRNA recognition by dsRBDs opens the possibility that this domain performs a direct readout of RNA sequence in the minor groove, allowing a global reconsideration of the principles describing dsRNA recognition by dsRBDs. We review in this article the current structural and molecular knowledge on dsRBDs, emphasizing the intricate relationship between the amino acid sequence, the structure of the domain and its RNA recognition capacity. We especially focus on the molecular determinants of dsRNA recognition and describe how sequence discrimination can be achieved by this type of domain. Content Type Journal Article Category Review Pages 1-21 DOI 10.1007/s00018-012-1119-x Authors Grégoire Masliah, Institute of Molecular Biology and Biophysics, ETH Zurich, Schafmattstrasse 20, 8093 Zürich, Switzerland Pierre Barraud, Institute of Molecular Biology and Biophysics, ETH Zurich, Schafmattstrasse 20, 8093 Zürich, Switzerland Frédéric H. -T. Allain, Institute of Molecular Biology and Biophysics, ETH Zurich, Schafmattstrasse 20, 8093 Zürich, Switzerland Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Melanoblasts are a particular type of cell that displays extensive cellular proliferation during development to contribute to the skin. There are only a few melanoblast founders, initially located just dorsal to the neural tube, and they sequentially colonize the dermis, epidermis, and hair follicles. In each compartment, melanoblasts are exposed to a wide variety of developmental cues that regulate their expansion. The colonization of the dermis and epidermis by melanoblasts involves substantial proliferation to generate thousands of cells or more from a few founders within a week of development. This review addresses the cellular and molecular events occurring during melanoblast development. We focus on intrinsic and extrinsic factors that control melanoblast proliferation. We also present a robust mathematical model for estimating the doubling-time of dermal and epidermal melanoblasts for all coat color phenotypes from black to white. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1112-4 Authors Lionel Larue, Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, 91405 Orsay, France Florian de Vuyst, Centre de Mathématiques et de leurs applications, CNRS UMR 8536, Ecole Normale Supérieure de Cachan, 94235 Cachan cedex, France Véronique Delmas, Institut Curie, Centre de Recherche, Developmental Genetics of Melanocytes, 91405 Orsay, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    As master gene regulators, microRNAs are involved in diverse cellular pathways. It is well known that microRNAs are often dysregulated in many types of cancer and other human diseases. In cancer, microRNAs may function as oncogenes or tumor suppressors. Interestingly, recent evidence suggests that microRNA-mediated gene regulation interconnects with the Akt pathway, forming an Akt–microRNA regulatory network. MicroRNAs and Akt in this network work together to exert their cellular functions. Thus, a better understanding of this Akt–microRNA regulatory network is critical to successful targeting of the PI3K/Akt pathway for cancer therapy. We review recent advances in the understanding of how microRNAs affect Akt activity as well as how microRNAs are regulated through the Akt pathway. We also briefly discuss the clinical implication of gene regulation mediated through Akt-associated microRNAs. Content Type Journal Article Category Multi-author review Pages 1-12 DOI 10.1007/s00018-012-1129-8 Authors Min Xu, Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001 Jiangsu, People’s Republic of China Yin-Yuan Mo, Cancer Institute, University of Mississippi Medical Center, 2500 N State St, Guyton 2, Suite G651, Jackson, MS 39216-4505, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Inteins catalyze a post-translational modification known as protein splicing, where the intein removes itself from a precursor protein and concomitantly ligates the flanking protein sequences with a peptide bond. Over the past two decades, inteins have risen from a peculiarity to a rich source of applications in biotechnology, biomedicine, and protein chemistry. In this review, we focus on developments of intein-related research spanning the last 5 years, including the three different splicing mechanisms and their molecular underpinnings, the directed evolution of inteins towards improved splicing in exogenous protein contexts, as well as novel applications of inteins for cell biology and protein engineering, which were made possible by a clearer understanding of the protein splicing mechanism. Content Type Journal Article Category Review Pages 1-22 DOI 10.1007/s00018-012-1120-4 Authors Gerrit Volkmann, Institute of Biochemistry, University of Münster, Wilhelm-Klemm-Str. 2, 48149 Münster, Germany Henning D. Mootz, Institute of Biochemistry, University of Münster, Wilhelm-Klemm-Str. 2, 48149 Münster, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    When plants are subjected to high metal exposure, different plant species take different strategies in response to metal-induced stress. Largely, plants can be distinguished in four groups: metal-sensitive species, metal-resistant excluder species, metal-tolerant non-hyperaccumulator species, and metal-hypertolerant hyperaccumulator species, each having different molecular mechanisms to accomplish their resistance/tolerance to metal stress or reduce the negative consequences of metal toxicity. Plant responses to heavy metals are molecularly regulated in a process called metal homeostasis, which also includes regulation of the metal-induced reactive oxygen species (ROS) signaling pathway. ROS generation and signaling plays an important duel role in heavy metal detoxification and tolerance. In this review, we will compare the different molecular mechanisms of nutritional (Zn) and non-nutritional (Cd) metal homeostasis between metal-sensitive and metal-adapted species. We will also include the role of metal-induced ROS signal transduction in this comparison, with the aim to provide a comprehensive overview on how plants cope with Zn/Cd stress at the molecular level. Content Type Journal Article Category Multi-author review Pages 1-20 DOI 10.1007/s00018-012-1089-z Authors Ya-Fen Lin, Laboratory of Genetics, Wageningen University, Droevendaalsesteeg 1, 6708 PB Wageningen, The Netherlands Mark G. M. Aarts, Laboratory of Genetics, Wageningen University, Droevendaalsesteeg 1, 6708 PB Wageningen, The Netherlands Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Centrosomes are organelles involved in generating and organizing the interphase microtubule cytoskeleton, mitotic spindles and cilia. At the centrosome core are a pair of centrioles, structures that act as the duplicating elements of this organelle. Centrioles function to recruit and organize pericentriolar material which nucleates microtubules. While centrioles are relatively simple in construction, the mechanics of centriole biogenesis remain an important yet poorly understood process. More mysterious still are the regulatory mechanisms that oversee centriole assembly. The fidelity of centriole duplication is critical as defects in either the assembly or number of centrioles promote aneuploidy, primary microcephaly, birth defects, ciliopathies and tumorigenesis. In addition, some pathogens employ mechanisms to promote centriole overduplication to the detriment of the host cell. This review summarizes our current understanding of this important topic, highlighting the need for further study if new therapeutics are to be developed to treat diseases arising from defects of centrosome duplication. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-1102-6 Authors Christopher W. Brownlee, Department of Cellular and Molecular Medicine, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA Gregory C. Rogers, Department of Cellular and Molecular Medicine, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Estrogen (E 2 ) regulates spermatogenesis, yet its direct target genes have not been identified in the testis. Here, we cloned the proximal 5′ flanking region of the mouse fatty acid amide hydrolase ( faah ) gene upstream of the luciferase reporter gene, and demonstrated its promoter activity and E 2 inducibility in primary mouse Sertoli cells. Specific mutations in the E 2 response elements (ERE) of the faah gene showed that two proximal ERE sequences (ERE2/3) are essential for E 2 -induced transcription, and chromatin immunoprecipitation experiments showed that E 2 induced estrogen receptor β binding at ERE2/3 sites in the faah promoter in vivo. Moreover, the histone demethylase LSD1 was found to be associated with ERE2/3 sites and to play a role in mediating E 2 induction of FAAH expression. E 2 induced epigenetic modifications at the faah proximal promoter compatible with transcriptional activation by remarkably decreasing methylation of both DNA at CpG site and histone H3 at lysine 9. Finally, FAAH silencing abolished E 2 protection against apoptosis induced by the FAAH substrate anandamide. Taken together, our results identify FAAH as the first direct target of E 2 . Content Type Journal Article Category Research Article Pages 1-14 DOI 10.1007/s00018-012-1074-6 Authors Paola Grimaldi, Department of Public Health and Cellular Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy Mariangela Pucci, Department of Biomedical Sciences, University of Teramo, Piazza A. Moro, 45, 64100 Teramo, Italy Sara Di Siena, Department of Public Health and Cellular Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy Daniele Di Giacomo, Department of Public Health and Cellular Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy Valentina Pirazzi, Department of Biomedical Sciences, University of Teramo, Piazza A. Moro, 45, 64100 Teramo, Italy Raffaele Geremia, Department of Public Health and Cellular Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy Mauro Maccarrone, Department of Biomedical Sciences, University of Teramo, Piazza A. Moro, 45, 64100 Teramo, Italy Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Store-operated Ca 2+ entry describes the phenomenon that connects a depletion of internal Ca 2+ stores to an activation of plasma membrane-located Ca 2+ selective ion channels. Tremendous progress towards the underlying molecular mechanism came with the discovery of the two respective limiting components, STIM and Orai. STIM1 represents the ER-located Ca 2+ sensor and transmits the signal of store depletion to the plasma membrane. Here it couples to and activates Orai, the highly Ca 2+ -selective pore-forming subunit of Ca 2+ release-activated Ca 2+ channels. In this review, we focus on the molecular steps that these two proteins undergo from store-depletion to their coupling, the activation, and regulation of Ca 2+ currents. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-1072-8 Authors Martin Muik, Institute of Biophysics, University of Linz, Gruberstrasse 40, 4020 Linz, Austria Rainer Schindl, Institute of Biophysics, University of Linz, Gruberstrasse 40, 4020 Linz, Austria Marc Fahrner, Institute of Biophysics, University of Linz, Gruberstrasse 40, 4020 Linz, Austria Christoph Romanin, Institute of Biophysics, University of Linz, Gruberstrasse 40, 4020 Linz, Austria Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The non-classical Human leukocyte antigen G (HLA-G) differs from classical HLA class I molecules by its low genetic diversity, a tissue-restricted expression, the existence of seven isoforms, and immuno-inhibitory functions. Most of the known functions of HLA-G concern the membrane-bound HLA-G1 and soluble HLA-G5 isoforms, which present the typical structure of classical HLA class I molecule: a heavy chain of three globular domains α 1 –α 2 –α 3 non-covalently bound to β-2-microglobulin (B2M) and a peptide. Very little is known of the structural features and functions of other HLA-G isoforms or structural conformations other than B2M-associated HLA-G1 and HLA-G5. In the present work, we studied the capability of all isoforms to form homomultimers, and investigated whether they could bind to, and function through, the known HLA-G receptors LILRB1 and LILRB2. We report that all HLA-G isoforms may form homodimers, demonstrating for the first time the existence of HLA-G4 dimers. We also report that the HLA-G α 1 –α 3 structure, which constitutes the extracellular part of HLA-G2 and HLA-G6, binds the LILRB2 receptor but not LILRB1. This is the first report of a receptor for a truncated HLA-G isoform. Following up on this finding, we show that the α 1 –α 3 -Fc structure coated on agarose beads is tolerogenic and capable of prolonging the survival of skin allografts in B6-mice and in a LILRB2-transgenic mouse model. This study is the first proof of concept that truncated HLA-G isoforms could be used as therapeutic agents. Content Type Journal Article Category Research Article Pages 1-9 DOI 10.1007/s00018-012-1069-3 Authors Kiave-Yune HoWangYin, CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475 Paris, France Maria Loustau, CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475 Paris, France Juan Wu, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Georgia Health Sciences University, Augusta, GA 30912, USA Estibaliz Alegre, Department of Biochemistry, University Clinic of Navarra, Pamplona, Spain Marina Daouya, CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475 Paris, France Julien Caumartin, CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475 Paris, France Sylvie Sousa, CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475 Paris, France Anatolij Horuzsko, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Georgia Health Sciences University, Augusta, GA 30912, USA Edgardo D. Carosella, CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475 Paris, France Joel LeMaoult, CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475 Paris, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Insulin-like growth factors (IGFs) influence placental cell (cytotrophoblast) kinetics. We recently reported that the protein tyrosine phosphatase (PTP) SHP-2 positively regulates IGF actions in the placenta. In other systems, the closely related PTP, SHP-1, functions as a negative regulator of signaling events but its role in the placenta is still unknown. We examined the hypothesis that SHP-1 negatively regulates IGF actions in the human placenta. Immunohistochemical (IHC) analysis demonstrated that SHP-1 is abundant in cytotrophoblast. SHP-1 expression was decreased in first-trimester placental explants using siRNA; knockdown did not alter IGF-induced proliferation but it significantly enhanced proliferation in serum-free conditions, revealing that placental growth is endogenously regulated. Candidate regulators were determined by using antibody arrays, Western blotting, and IHC to examine the activation status of multiple receptor tyrosine kinases (RTKs) in SHP-1-depleted explants; amongst the alterations observed was enhanced activation of EGFR, suggesting that SHP-1 may interact with EGFR to inhibit proliferation. The EGFR tyrosine kinase inhibitor PD153035 reversed the elevated proliferation seen in the absence of SHP-1. This study demonstrates a role for SHP-1 in human trophoblast turnover and establishes SHP-1 as a negative regulator of EGFR activation. Targeting placental SHP-1 expression may provide therapeutic benefits in common pregnancy conditions with abnormal trophoblast proliferation. Content Type Journal Article Category Research Article Pages 1-12 DOI 10.1007/s00018-012-1067-5 Authors Karen Forbes, Maternal and Fetal Health Research Centre, Manchester Academic Health Sciences Centre, St Mary’s Hospital, University of Manchester, School of Biomedicine, Manchester, M13 9WL UK Laura Skinner, Maternal and Fetal Health Research Centre, Manchester Academic Health Sciences Centre, St Mary’s Hospital, University of Manchester, School of Biomedicine, Manchester, M13 9WL UK John D. Aplin, Maternal and Fetal Health Research Centre, Manchester Academic Health Sciences Centre, St Mary’s Hospital, University of Manchester, School of Biomedicine, Manchester, M13 9WL UK Melissa Westwood, Maternal and Fetal Health Research Centre, Manchester Academic Health Sciences Centre, St Mary’s Hospital, University of Manchester, School of Biomedicine, Manchester, M13 9WL UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The generation of specialized neural cells in the developing and postnatal central nervous system is a highly regulated process, whereby neural stem cells divide to generate committed neuronal progenitors, which then withdraw from the cell cycle and start to differentiate. Cell cycle checkpoints play a major role in regulating the balance between neural stem cell expansion and differentiation. Loss of tumor suppressors involved in checkpoint control can lead to dramatic alterations of neurogenesis, thus contributing to neoplastic transformation. Here we summarize and critically discuss the existing literature on the role of tumor suppressive pathways and their regulatory networks in the control of neurogenesis and transformation. Content Type Journal Article Category Review Pages 1-17 DOI 10.1007/s00018-012-1063-9 Authors Stefano Bartesaghi, Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD UK Paolo Salomoni, Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Cytonuclear signaling is essential for long-term alterations of cellular properties. Several pathways involving regulated nuclear accumulation of Ser/Thr kinases have been described but little is known about cytonuclear trafficking of tyrosine kinases. Proline-rich tyrosine kinase 2 (Pyk2) is a cytoplasmic non-receptor tyrosine kinase enriched in neurons and involved in functions ranging from synaptic plasticity to bone resorption, as well as in cancer. We previously showed the Ca 2+ -induced, calcineurin-dependent, nuclear localization of Pyk2. Here, we characterize the molecular mechanisms of Pyk2 cytonuclear localization in transfected PC12 cells. The 700–841 linker region of Pyk2 recapitulates its depolarization-induced nuclear accumulation. This region includes a nuclear export motif regulated by phosphorylation at residue S778, a substrate of cAMP-dependent protein kinase and calcineurin. Nuclear import is controlled by a previously identified sequence in the N-terminal domain and by a novel nuclear targeting signal in the linker region. Regulation of cytonuclear trafficking is independent of Pyk2 activity. The region regulating nuclear localization is absent from the non-neuronal shorter splice isoform of Pyk2. Our results elucidate the mechanisms of Ca 2+ -induced nuclear accumulation of Pyk2. They also suggest that Pyk2 nuclear accumulation is a novel type of signaling response that may contribute to specific long-term adaptations in neurons. Content Type Journal Article Category Research Article Pages 1-16 DOI 10.1007/s00018-012-1075-5 Authors Camille Faure, Inserm, UMR-S 839, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France Mariana Ramos, Inserm, UMR-S 839, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France Jean-Antoine Girault, Inserm, UMR-S 839, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    In eukaryotic cells, the shape of mitochondria can be tuned to various physiological conditions by a balance of fusion and fission processes termed mitochondrial dynamics. Mitochondrial dynamics controls not only the morphology but also the function of mitochondria, and therefore is crucial in many aspects of a cell’s life. Consequently, dysfunction of mitochondrial dynamics has been implicated in a variety of human diseases including cancer. Several proteins important for mitochondrial fusion and fission have been discovered over the past decade. However, there is emerging evidence that there are as yet unidentified proteins important for these processes and that the fusion/fission machinery is not completely conserved between yeast and vertebrates. The recent characterization of several mammalian proteins important for the process that were not conserved in yeast, may indicate that the molecular mechanisms regulating and controlling the morphology and function of mitochondria are more elaborate and complex in vertebrates. This difference could possibly be a consequence of different needs in the different cell types of multicellular organisms. Here, we review recent advances in the field of mitochondrial dynamics. We highlight and discuss the mechanisms regulating recruitment of cytosolic Drp1 to the mitochondrial outer membrane by Fis1, Mff, and MIEF1 in mammals and the divergences in regulation of mitochondrial dynamics between yeast and vertebrates. Content Type Journal Article Category Review Pages 1-26 DOI 10.1007/s00018-012-1066-6 Authors Jian Zhao, Department of Oncology-Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden Urban Lendahl, Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden Monica Nistér, Department of Oncology-Pathology, Karolinska Institutet, CCK R8:05, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansion in the amino-terminus of huntingtin (HTT). HD offers unique opportunities for promising RNA-based therapeutic approaches aimed at reducing mutant HTT expression, since the HD mutation is considered to be a “gain-of-function” mutation. Allele-specific strategies that preserve expression from the wild-type allele and reduce the levels of mutant protein would be of particular interest. Here, we have conducted proof-of-concept studies to demonstrate that spliceosome-mediated trans -splicing is a viable molecular strategy to specifically repair the HTT allele. We employed a dual plasmid transfection system consisting of a pre-mRNA trans -splicing module (PTM) containing HTT exon 1 and a HTT minigene to demonstrate that HTT exon 1 can be replaced in trans . We detected the presence of the trans -spliced RNA in which PTM exon 1 was correctly joined to minigene exons 2 and 3. Furthermore, exon 1 from the PTM was trans -spliced to the endogenous HTT pre-mRNA in cultured cells as well as disease-relevant models, including HD patient fibroblasts and primary neurons from a previously described HD mouse model. These results suggest that the repeat expansion of HTT can be repaired successfully not only in the context of synthetic minigenes but also within the context of HD neurons. Therefore, pre-mRNA trans -splicing may be a promising approach for the treatment of HD and other dominant genetic disorders. Content Type Journal Article Category Research Article Pages 1-14 DOI 10.1007/s00018-012-1083-5 Authors Hansjörg Rindt, Department of Veterinary Pathobiology, Life Sciences Center, University of Missouri, Room 471G, Columbia, MO 65211, USA Pei-Fen Yen, Department of Veterinary Pathobiology, Life Sciences Center, University of Missouri, Room 471G, Columbia, MO 65211, USA Christina N. Thebeau, Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA Troy S. Peterson, Interdisciplinary Neuroscience Program, University of Missouri, Columbia, MO 65211, USA Gary A. Weisman, Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA Christian L. Lorson, Department of Veterinary Pathobiology, Life Sciences Center, University of Missouri, Room 471G, Columbia, MO 65211, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Lung cancer is the leading cause of cancer death for both men and women worldwide. Since most of the symptoms found for lung cancer are nonspecific, diagnosis is mostly done at late and progressed stage with the consecutive poor therapy outcome. Effective early detection techniques are sorely needed. The emerging field of salivary diagnostics could provide scientifically credible, easy-to-use, non-invasive and cost-effective detection methods. Recent advances have allowed us to develop discriminatory salivary biomarkers for a variety of diseases from oral to systematic diseases. In this study, salivary transcriptomes of lung cancer patients were profiled and led to the discovery and pre-validation of seven highly discriminatory transcriptomic salivary biomarkers (BRAF, CCNI, EGRF, FGF19, FRS2, GREB1, and LZTS1). The logistic regression model combining five of the mRNA biomarkers (CCNI, EGFR, FGF19, FRS2, and GREB1) could differentiate lung cancer patients from normal control subjects, yielding AUC value of 0.925 with 93.75 % sensitivity and 82.81 % specificity in the pre-validation sample set. These salivary mRNA biomarkers possess the discriminatory power for the detection of lung cancer. This report provides the proof of concept of salivary biomarkers for the non-invasive detection of the systematic disease. These results poised the salivary biomarkers for the initiation of a multi-center validation in a definitive clinical context. Content Type Journal Article Category Research Article Pages 1-10 DOI 10.1007/s00018-012-1027-0 Authors Lei Zhang, School of Dentistry and Dental Research Institute, University of California, 10833 Le Conte Avenue, 73-024 CHS, Los Angeles, CA 90095, USA Hua Xiao, School of Dentistry and Dental Research Institute, University of California, 10833 Le Conte Avenue, 73-024 CHS, Los Angeles, CA 90095, USA Hui Zhou, School of Dentistry and Dental Research Institute, University of California, 10833 Le Conte Avenue, 73-024 CHS, Los Angeles, CA 90095, USA Silverio Santiago, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA Jay M. Lee, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA Edward B. Garon, Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA Jieping Yang, School of Dentistry and Dental Research Institute, University of California, 10833 Le Conte Avenue, 73-024 CHS, Los Angeles, CA 90095, USA Ole Brinkmann, School of Dentistry and Dental Research Institute, University of California, 10833 Le Conte Avenue, 73-024 CHS, Los Angeles, CA 90095, USA Xinmin Yan, School of Dentistry and Dental Research Institute, University of California, 10833 Le Conte Avenue, 73-024 CHS, Los Angeles, CA 90095, USA David Akin, School of Dentistry and Dental Research Institute, University of California, 10833 Le Conte Avenue, 73-024 CHS, Los Angeles, CA 90095, USA David Chia, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA David Elashoff, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA No-Hee Park, School of Dentistry and Dental Research Institute, University of California, 10833 Le Conte Avenue, 73-024 CHS, Los Angeles, CA 90095, USA David T. W. Wong, School of Dentistry and Dental Research Institute, University of California, 10833 Le Conte Avenue, 73-024 CHS, Los Angeles, CA 90095, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Protein quality control is vital for all living cells and sophisticated molecular mechanisms have evolved to prevent the excessive accumulation of unfolded proteins. High-temperature requirement A (HtrA) proteases have been identified as important ATP-independent quality-control factors in most species. HtrA proteins harbor a serine-protease domain and at least one peptide-binding PDZ domain to ensure efficient removal of misfolded or damaged proteins. One distinctive property of HtrAs is their ability to assemble into complex oligomers. Whereas all examined HtrAs are capable of forming pyramidal 3-mers, higher-order complexes consisting of up to 24 molecules have been reported. Tight control of chaperone and protease function is of pivotal importance in preventing deleterious HtrA-protease activity. In recent years, structural biology provided detailed insights into the molecular basis of the regulatory mechanisms, which include unique intramolecular allosteric signaling cascades and the dynamic switching of oligomeric states of HtrA proteins. Based on these results, functional models for many family members have been developed. The HtrA protein family represents a remarkable example of how structural and functional diversity is attained from the assembly of simple molecular building blocks. Content Type Journal Article Category Review Pages 1-15 DOI 10.1007/s00018-012-1076-4 Authors Guido Hansen, Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23538 Lübeck, Germany Rolf Hilgenfeld, Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23538 Lübeck, Germany Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Structural symmetry is observed in the majority of fundamental protein folds and gene duplication and fusion evolutionary processes are postulated to be responsible. However, convergent evolution leading to structural symmetry has also been proposed; additionally, there is debate regarding the extent to which exact primary structure symmetry is compatible with efficient protein folding. Issues of symmetry in protein evolution directly impact strategies for de novo protein design as symmetry can substantially simplify the design process. Additionally, when considering gene duplication and fusion in protein evolution, there are two competing models: “emergent architecture” and “conserved architecture”. Recent experimental work has shed light on both the evolutionary process leading to symmetric protein folds as well as the ability of symmetric primary structure to efficiently fold. Such studies largely support a “conserved architecture” evolutionary model, suggesting that complex protein architecture was an early evolutionary achievement involving oligomerization of smaller polypeptides. Content Type Journal Article Category Review Pages 1-8 DOI 10.1007/s00018-012-1077-3 Authors Michael Blaber, Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call St., Tallahassee, FL 32306-4300, USA Jihun Lee, Celltrion Inc., 13-1 Songdo-dong, Yeonsu-gu, Incheon, 406-840 Korea Liam Longo, Department of Biomedical Sciences, College of Medicine, Florida State University, 1115 West Call St., Tallahassee, FL 32306-4300, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Many components and pathways transducing multifaceted and deleterious effects of stress stimuli remain ill-defined. The Ran-binding protein 2 (RanBP2) interactome modulates the expression of a range of clinical and cell-context-dependent manifestations upon a variety of stressors. We examined the role of Ranbp2 haploinsufficiency on cellular and metabolic manifestations linked to tyrosine-hydroxylase (TH + ) dopaminergic neurons and glial cells of the brain and retina upon acute challenge to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a parkinsonian neurotoxin, which models facets of Parkinson disease. MPTP led to stronger akinetic parkinsonism and slower recovery in Ranbp2 +/− than wild-type mice without viability changes of brain TH + -neurons of either genotype, with the exception of transient nuclear atypia via changes in chromatin condensation of Ranbp2 +/− TH + -neurons. Conversely, the number of wild-type retinal TH + -amacrine neurons compared to Ranbp2 +/− underwent milder declines without apoptosis followed by stronger recoveries without neurogenesis. These phenotypes were accompanied by a stronger rise of EdU + -proliferative cells and non-proliferative gliosis of GFAP + -Müller cells in wild-type than Ranbp2 +/− that outlasted the MPTP-insult. Finally, MPTP-treated wild-type and Ranbp2 +/− mice present distinct metabolic footprints in the brain or selective regions thereof, such as striatum, that are supportive of RanBP2-mediated regulation of interdependent metabolic pathways of lysine, cholesterol, free-fatty acids, or their β-oxidation. These studies demonstrate contrasting gene-environment phenodeviances and roles of Ranbp2 between dopaminergic and glial cells of the brain and retina upon oxidative stress-elicited signaling and factors triggering a continuum of metabolic and cellular manifestations and proxies linked to oxidative stress, and chorioretinal and neurological disorders such as Parkinson. Content Type Journal Article Category Research Article Pages 1-17 DOI 10.1007/s00018-012-1071-9 Authors Kyoung-in Cho, Department of Ophthalmology, Duke University Medical Center, DUEC 3802, 2351 Erwin Road, Durham, NC 27710, USA Kelly Searle, Department of Ophthalmology, Duke University Medical Center, DUEC 3802, 2351 Erwin Road, Durham, NC 27710, USA Mason Webb, Department of Ophthalmology, Duke University Medical Center, DUEC 3802, 2351 Erwin Road, Durham, NC 27710, USA Haiqing Yi, Department of Ophthalmology, Duke University Medical Center, DUEC 3802, 2351 Erwin Road, Durham, NC 27710, USA Paulo A. Ferreira, Department of Ophthalmology, Duke University Medical Center, DUEC 3802, 2351 Erwin Road, Durham, NC 27710, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The thyroid hormone 3,3 ′ ,5-triiodo- l -thyronine (T 3 ) mediates several physiological processes, including embryonic development, cellular differentiation, metabolism, and the regulation of cell proliferation. Thyroid hormone receptors (TRs) generally act as heterodimers with the retinoid X receptor (RXR) to regulate target genes. In addition to their developmental and metabolic functions, TRs have been shown to play a tumor suppressor role, suggesting that their aberrant expression can lead to tumor transformation. Conversely, recent reports have shown an association between overexpression of wild-type TRs and tumor metastasis. Signaling crosstalk between T 3 /TR and other pathways or specific TR coregulators appear to affect tumor development. Since TR actions are complex as well as cell context-, tissue- and time-specific, aberrant expression of the various TR isoforms has different effects during diverse tumorigenesis. Therefore, elucidation of the T 3 /TR signaling mechanisms in cancers should facilitate the identification of novel therapeutic targets. This review provides a summary of recent studies focusing on the role of TRs in hepatocellular carcinomas (HCCs). Content Type Journal Article Category Review Pages 1-22 DOI 10.1007/s00018-012-1146-7 Authors Sheng-Ming Wu, Department of Biochemistry, College of Medicine, Chang-Gung University, 259 Wen-hwa 1 Road, Taoyuan, 333 Taiwan Wan-Li Cheng, Department of Biochemistry, College of Medicine, Chang-Gung University, 259 Wen-hwa 1 Road, Taoyuan, 333 Taiwan Crystal D. Lin, Pre-med Program, Pacific Union College, Angwin, CA 94508, USA Kwang-Huei Lin, Department of Biochemistry, College of Medicine, Chang-Gung University, 259 Wen-hwa 1 Road, Taoyuan, 333 Taiwan Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Anti-apoptotic Bcl-2-family members not only neutralize pro-apoptotic proteins but also directly regulate intracellular Ca 2+ signaling from the endoplasmic reticulum (ER), critically controlling cellular health, survival, and death initiation. Furthermore, distinct Bcl-2-family members may selectively regulate inositol 1,4,5-trisphosphate receptor (IP 3 R): Bcl-2 likely acts as an endogenous inhibitor of the IP 3 R, preventing pro-apoptotic Ca 2+ transients, while Bcl-X L likely acts as an endogenous IP 3 R-sensitizing protein promoting pro-survival Ca 2+ oscillations. Furthermore, distinct functional domains in Bcl-2 and Bcl-X L may underlie the divergence in IP 3 R regulation. The Bcl-2 homology (BH) 4 domain, which targets the central modulatory domain of the IP 3 R, is likely to be Bcl-2’s determining factor. In contrast, the hydrophobic cleft targets the C-terminal Ca 2+ -channel tail and might be more crucial for Bcl-X L ’s function. Furthermore, one amino acid critically different in the sequence of Bcl-2’s and Bcl-X L ’s BH4 domains underpins their selective effect on Ca 2+ signaling and distinct biological properties of Bcl-2 versus Bcl-X L . This difference is evolutionary conserved across five classes of vertebrates and may represent a fundamental divergence in their biological function. Moreover, these insights open novel avenues to selectively suppress malignant Bcl-2 function in cancer cells by targeting its BH4 domain, while maintaining essential Bcl-X L functions in normal cells. Thus, IP 3 R-derived molecules that mimic the BH4 domain’s binding site on the IP 3 R may function synergistically with BH3-mimetic molecules selectivity suppressing Bcl-2’s proto-oncogenic activity. Finally, a more general role for the BH4 domain on IP 3 Rs, rather than solely anti-apoptotic, may not be excluded as part of a complex network of molecular interactions. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1118-y Authors Giovanni Monaco, Laboratory of Molecular and Cellular Signaling, Department Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O/N-1 bus 802, 3000 Leuven, Belgium Tim Vervliet, Laboratory of Molecular and Cellular Signaling, Department Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O/N-1 bus 802, 3000 Leuven, Belgium Haidar Akl, Laboratory of Molecular and Cellular Signaling, Department Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O/N-1 bus 802, 3000 Leuven, Belgium Geert Bultynck, Laboratory of Molecular and Cellular Signaling, Department Cellular and Molecular Medicine, KU Leuven, Campus Gasthuisberg O/N-1 bus 802, 3000 Leuven, Belgium Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Notch signaling plays crucial roles in fate determination and the differentiation of neural stem cells in embryonic and adult brains. It is now clear that the notch pathway is under more complex and dynamic regulation than previously thought. To understand the functional details of notch signaling more precisely, it is important to reveal when, where, and how notch signaling is dynamically communicated between cells, for which the visualization of notch signaling is essential. In this review, we introduce recent technical advances in the visualization of notch signaling during neural development and in the adult brain, and we discuss the physiological significance of dynamic regulation of notch signaling. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1151-x Authors Itaru Imayoshi, Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, 606-8507 Japan Hiromi Shimojo, Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, 606-8507 Japan Masayuki Sakamoto, Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, 606-8507 Japan Toshiyuki Ohtsuka, Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, 606-8507 Japan Ryoichiro Kageyama, Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto, 606-8507 Japan Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    The Eyes Absent (EYA) proteins, first described in the context of fly eye development, are now implicated in processes as disparate as organ development, innate immunity, DNA damage repair, photoperiodism, angiogenesis, and cancer metastasis. These functions are associated with an unusual combination of biochemical activities: tyrosine phosphatase and threonine phosphatase activities in separate domains, and transactivation potential when associated with a DNA-binding partner. EYA mutations are linked to multiorgan developmental disorders, as well as to adult diseases ranging from dilated cardiomyopathy to late-onset sensorineural hearing loss. With the growing understanding of EYA biochemical and cellular activity, biological function, and association with disease, comes the possibility that the EYA proteins are amenable to the design of targeted therapeutics. The availability of structural information, direct links to disease states, available animal models, and the fact that they utilize unconventional reaction mechanisms that could allow specificity, suggest that EYAs are well-positioned for drug discovery efforts. This review provides a summary of EYA structure, activity, and function, as they relate to development and disease, with particular emphasis on recent findings. Content Type Journal Article Category Review Pages 1-17 DOI 10.1007/s00018-012-1144-9 Authors Emmanuel Tadjuidje, Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA Rashmi S. Hegde, Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Recent work on the MACPF/CDC superfamily of pore-forming proteins has focused on the structural analysis of monomers and pore-forming oligomeric complexes. We set the family of proteins in context and highlight aspects of their function which the direct and exclusive equation of oligomers with pores fails to explain. Starting with a description of the distribution of MACPF/CDC proteins across the domains of life, we proceed to show how their evolutionary relationships can be understood on the basis of their structural homology and re-evaluate models for pore formation by perforin, in particular. We furthermore highlight data showing the role of incomplete oligomeric rings (arcs) in pore formation and how this can explain small pores generated by oligomers of proteins belonging to the family. We set this in the context of cell biological and biophysical data on the proteins’ function and discuss how this helps in the development of an understanding of how they act in processes such as apicomplexan parasites gliding through cells and exiting from cells. Content Type Journal Article Category Review Pages 1-16 DOI 10.1007/s00018-012-1153-8 Authors Robert J. C. Gilbert, Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN UK Miha Mikelj, Department of Biology, Biotechnical Faculty, University of Ljubljana, Večna pot 111, 1000 Ljubljana, Slovenia Mauro Dalla Serra, National Research Council, Institute of Biophysics and Bruno Kessler Foundation, via alla Cascata 56/C, 38123 Trento, Italy Christopher J. Froelich, Department of Medicine, NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA Gregor Anderluh, Department of Biology, Biotechnical Faculty, University of Ljubljana, Večna pot 111, 1000 Ljubljana, Slovenia Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Effective antiviral immunity depends on accurate recognition of viral RNAs by the innate immune system. Double-stranded RNA (dsRNA) often accumulates in virally infected cells and was initially considered a unique viral signature that was sufficient to initiate antiviral response through dsRNA receptors and dsRNA-dependent effectors such as Toll-like receptor 3, retinoic acid inducible gene-1, protein kinase RNA-activated and oligoadenylate synthetase. However, dsRNA is also present in many cellular RNAs, raising a question of how these receptors and effectors discriminate between viral and cellular dsRNAs. Accumulating evidence suggests that innate immune sensors detect not only dsRNA structure but also other and often multiple features of RNA such as length, sequence, cellular location, post-transcriptional processing and modification, which are divergent between viral and cellular RNAs. This review summarizes recent findings on the substrate specificities of a few selected dsRNA-dependent effectors and receptors, which have revealed more complex mechanisms involved in cellular discrimination between self and non-self RNA. Content Type Journal Article Category Review Pages 1-15 DOI 10.1007/s00018-012-1149-4 Authors Alys Peisley, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA Sun Hur, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Radiation-induced genomic instability is a modification of the cell genome found in the progeny of irradiated somatic and germ cells but that is not confined on the initial radiation-induced damage and may occur de novo many generations after irradiation. Genomic instability in the germ line does not follow Mendelian segregation and may have unpredictable outcomes in every succeeding generation. This phenomenon, for which there is extensive experimental data and some evidence in human populations exposed to ionising radiation, is not taken into account in health risk assessments. It poses an unknown morbidity/mortality burden. Based on experimental data derived over the last 20 years (up to January 2012) six mechanistic explanations for the phenomenon have been proposed in the peer-reviewed literature. This article compares these hypotheses with the empirical data to test their fitness to explain the phenomenon. As a conclusion, the most convincing explanation of radiation-induced genomic instability attributes it to an irreversible regulatory change in the dynamic interaction network of the cellular gene products, as a response to non-specific molecular damage, thus entailing the rejection of the machine metaphor for the cell in favour of one appropriate to a complex dissipative dynamic system, such as a whirlpool. It is concluded that in order to evaluate the likely morbidity/mortality associated with radiation-induced genomic instability, it will be necessary to study the damage to processes by radiation rather than damage to molecules. Content Type Journal Article Category Visions and reflections Pages 1-10 DOI 10.1007/s00018-012-1148-5 Authors Andrei V. Karotki, Radiation Group, International Agency for Research on Cancer, International Agency for Research on Cancer, 150 Cours A. Thomas, 69372 Lyon, France Keith Baverstock, Department of Environmental Science, University of Eastern Finland, Kuopio Campus, PL 1627, 70211 Kuopio, Finland Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Myocardial stem cell therapies are emerging as novel therapeutic paradigms for myocardial repair, but are hampered by the lack of sources for autologous human cardiomyocytes. An exciting development in the field of cardiovascular regenerative medicine is the ability to reprogram adult somatic cells into pluripotent stem cell lines (induced pluripotent stem cells, iPSCs) and to coax their differentiation into functional cardiomyocytes. This technology holds great promise for the emerging disciplines of personalized and regenerative medicine, because of the ability to derive patient-specific iPSCs that could potentially elude the immune system. The current review describes the latest techniques of generating iPSCs as well as the methods used to direct their differentiation towards the cardiac lineage. We then detail the unique potential as well as the possible hurdles on the road to clinical utilizing of the iPSCs derived cardiomyocytes in the emerging field of cardiovascular regenerative medicine. Content Type Journal Article Category Review Pages 3285-3299 DOI 10.1007/s00018-012-1078-2 Authors Limor Zwi-Dantsis, The Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion’s Faculty of Medicine, Technion–Israel Institute of Technology, POB 9649, 31096 Haifa, Israel Lior Gepstein, The Sohnis Family Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, The Rappaport Faculty of Medicine and Research Institute, Technion’s Faculty of Medicine, Technion–Israel Institute of Technology, POB 9649, 31096 Haifa, Israel Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X Journal Volume Volume 69 Journal Issue Volume 69, Number 19

Description:    The merging of the maternal and paternal genomes into a single pronucleus after fertilization is accompanied by a remarkable reconfiguration of chromatin in the newly formed zygote. The first stages of embryonic chromatin remodeling take place in the absence of ongoing transcription, during a species-specific developmental time-frame. Once post-fertilization chromatin states are organized, zygotic genome activation (ZGA) is initiated, and embryonic transcripts gradually take control of development. We review here transitions in chromatin modifications associated with the onset of ZGA, and the role of transcription factors and DNA motifs in the regulation of ZGA. We propose a model of sequential chromatin remodeling events preceding ZGA, leading to the onset of embryonic transcription. Content Type Journal Article Category Review Pages 1-13 DOI 10.1007/s00018-012-1143-x Authors Olga Østrup, Stem Cell Epigenetics Laboratory, and Norwegian Center for Stem Cell Research, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway Ingrid S. Andersen, Stem Cell Epigenetics Laboratory, and Norwegian Center for Stem Cell Research, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway Philippe Collas, Stem Cell Epigenetics Laboratory, and Norwegian Center for Stem Cell Research, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo, Norway Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Nesfatin-1 is an anorexic nucleobindin-2 (NUCB2)-derived hypothalamic peptide. It controls feeding behavior, water intake, and glucose homeostasis. If intracerebrally administered, it induces hypertension, thus suggesting a role in central cardiovascular control. However, it is not known whether it is able to directly control heart performance. We aimed to verify the hypothesis that, as in the case of other hypothalamic satiety peptides, Nesfatin-1 acts as a peripheral cardiac modulator. By western blotting and QT-PCR, we identified the presence of both Nesfatin-1 protein and NUCB2 mRNA in rat cardiac extracts. On isolated and Langendorff-perfused rat heart preparations, we found that exogenous Nesfatin-1 depresses contractility and relaxation without affecting coronary motility. These effects did not involve Nitric oxide, but recruited the particulate guanylate cyclase (pGC) known as natriuretic peptide receptor A (NPR-A), protein kinase G (PKG) and extracellular signal-regulated kinases1/2 (ERK1/2). Co-immunoprecipitation and bioinformatic analyses supported an interaction between Nesfatin-1 and NPR-A. Lastly, we preliminarily observed, through post-conditioning experiments, that Nesfatin-1 protects against ischemia/reperfusion (I/R) injury by reducing infarct size, lactate dehydrogenase release, and postischemic contracture. This protection involves multiple prosurvival kinases such as PKCε, ERK1/2, signal transducer and activator of transcription 3, and mitochondrial K ATP channels. It also ameliorates contractility recovery. Our data indicate that: (1) the heart expresses Nesfatin-1, (2) Nesfatin-1 directly affects myocardial performance, possibly involving pGC-linked NPR-A, the pGC/PKG pathway, and ERK1/2, (3) the peptide protects the heart against I/R injury. Results pave the way to include Nesfatin-1 in the neuroendocrine modulators of the cardiac function, also encouraging the clarification of its clinical potential in the presence of nutrition-dependent physio-pathologic cardiovascular diseases. Content Type Journal Article Category Research article Pages 1-15 DOI 10.1007/s00018-012-1138-7 Authors T. Angelone, Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende, CS, Italy E. Filice, Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende, CS, Italy T. Pasqua, Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende, CS, Italy N. Amodio, Department of Experimental and Clinical Medicine, University of Catanzaro Magna Græcia, Catanzaro, Italy M. Galluccio, Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende, CS, Italy G. Montesanti, Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende, CS, Italy A. M. Quintieri, Department of Cell Biology, University of Calabria, 87030 Arcavacata di Rende, CS, Italy M. C. Cerra, Laboratory of Cardiovascular Physiology, Department of Pharmaco-Biology, University of Calabria, 87030 Arcavacata di Rende, CS, Italy Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    In cardiac muscle, the sarcolemmal sodium/potassium ATPase is the principal quantitative means of active transport at the myocyte cell surface, and its activity is essential for maintaining the trans-sarcolemmal sodium gradient that drives ion exchange and transport processes that are critical for cardiac function. The 72-residue phosphoprotein phospholemman regulates the sodium pump in the heart: unphosphorylated phospholemman inhibits the pump, and phospholemman phosphorylation increases pump activity. Phospholemman is subject to a remarkable plethora of post-translational modifications for such a small protein: the combination of three phosphorylation sites, two palmitoylation sites, and one glutathionylation site means that phospholemman integrates multiple signaling events to control the cardiac sodium pump. Since misregulation of cytosolic sodium contributes to contractile and metabolic dysfunction during cardiac failure, a complete understanding of the mechanisms that control the cardiac sodium pump is vital. This review explores our current understanding of these mechanisms. Content Type Journal Article Category Review Pages 1-24 DOI 10.1007/s00018-012-1134-y Authors W. Fuller, Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, College of Medicine Dentistry and Nursing, University of Dundee, Dundee, UK L. B. Tulloch, Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, College of Medicine Dentistry and Nursing, University of Dundee, Dundee, UK M. J. Shattock, Cardiovascular Division, King’s College London, London, UK S. C. Calaghan, School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT UK J. Howie, Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, College of Medicine Dentistry and Nursing, University of Dundee, Dundee, UK K. J. Wypijewski, Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, College of Medicine Dentistry and Nursing, University of Dundee, Dundee, UK Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Members of the tristetraprolin (TTP/TIS11) family are important RNA-binding proteins initially characterized as mediators of mRNA degradation. They act via their interaction with AU-rich elements present in the 3′UTR of regulated transcripts. However, it is progressively appearing that the different steps of mRNA processing and fate including transcription, splicing, polyadenylation, translation, and degradation are coordinately regulated by multifunctional integrator proteins that possess a larger panel of functions than originally anticipated. Tristetraprolin and related proteins are very good examples of such integrators. This review gathers the present knowledge on the functions of this family of RNA-binding proteins, including their role in AU-rich element-mediated mRNA decay and focuses on recent advances that support the concept of their broader involvement in distinct steps of mRNA biogenesis and degradation. Content Type Journal Article Category Review Pages 1-14 DOI 10.1007/s00018-012-1150-y Authors Delphine Ciais, Institut National de la Santé et de la Recherche Médicale (INSERM) U1036, 17 rue des Martyrs, 38054 Grenoble Cedex 9, France Nadia Cherradi, Institut National de la Santé et de la Recherche Médicale (INSERM) U1036, 17 rue des Martyrs, 38054 Grenoble Cedex 9, France Jean-Jacques Feige, Institut National de la Santé et de la Recherche Médicale (INSERM) U1036, 17 rue des Martyrs, 38054 Grenoble Cedex 9, France Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X

Description:    Recent research into the role of microRNA (miR) in the immune system has identified the miR-29 family as critical regulators of key processes in adaptive immunity. The miR-29 family consists of four members with shared regulatory capacity, namely miR-29a, miR-29b-1, miR-29b-2 and miR-29c. Being expressed in both T and B cells, as well as the main accessory cell types of thymic epithelium and dendritic cells, the miR-29 family has been identified as a putative regulator of immunity due to the predicted suppression of key immunological pathways. The generation of a series of in vivo molecular tools targeting the miR-29 family has identified the critical role of these miR in setting the molecular threshold for three central events in adaptive immunity: (1) control over thymic production of T cells by modulating the threshold for infection-associated thymic involution, (2) creating a neutral threshold for T cell polarization following activation, and (3) setting the threshold for B cell oncogenic transformation. These results identify the miR-29 family as potent immune modulators which have already been exploited through the evolution of a viral mimic and could potentially be exploited further for therapeutic intervention. Content Type Journal Article Category Multi-author review Pages 1-9 DOI 10.1007/s00018-012-1124-0 Authors Adrian Liston, Autoimmune Genetics Laboratory, VIB and University of Leuven, Leuven, Belgium Aikaterini S. Papadopoulou, Center for Human Genetics, VIB and University of Leuven, Leuven, Belgium Dina Danso-Abeam, Autoimmune Genetics Laboratory, VIB and University of Leuven, Leuven, Belgium James Dooley, Autoimmune Genetics Laboratory, VIB and University of Leuven, Leuven, Belgium Journal Cellular and Molecular Life Sciences Online ISSN 1420-9071 Print ISSN 1420-682X