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  • 1
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    Ubiquitin is phosphorylated by PINK1 to activate parkin (2014)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2014-05-03
    Beschreibung: PINK1 (PTEN induced putative kinase 1) and PARKIN (also known as PARK2) have been identified as the causal genes responsible for hereditary recessive early-onset Parkinsonism. PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. PINK1 acts as an upstream factor for parkin and is essential both for the activation of latent E3 parkin activity and for recruiting parkin onto depolarized mitochondria. Recently, mechanistic insights into mitochondrial quality control mediated by PINK1 and parkin have been revealed, and PINK1-dependent phosphorylation of parkin has been reported. However, the requirement of PINK1 for parkin activation was not bypassed by phosphomimetic parkin mutation, and how PINK1 accelerates the E3 activity of parkin on damaged mitochondria is still obscure. Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. Unexpectedly, phosphomimetic ubiquitin bypassed PINK1-dependent activation of a phosphomimetic parkin mutant in cells. Furthermore, phosphomimetic ubiquitin accelerates discharge of the thioester conjugate formed by UBCH7 (also known as UBE2L3) and ubiquitin (UBCH7 approximately ubiquitin) in the presence of parkin in vitro, indicating that it acts allosterically. The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koyano, Fumika -- Okatsu, Kei -- Kosako, Hidetaka -- Tamura, Yasushi -- Go, Etsu -- Kimura, Mayumi -- Kimura, Yoko -- Tsuchiya, Hikaru -- Yoshihara, Hidehito -- Hirokawa, Takatsugu -- Endo, Toshiya -- Fon, Edward A -- Trempe, Jean-Francois -- Saeki, Yasushi -- Tanaka, Keiji -- Matsuda, Noriyuki -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Jun 5;510(7503):162-6. doi: 10.1038/nature13392. Epub 2014 Jun 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561, Japan. ; Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, The University of Tokushima, Tokushima 770-8503, Japan. ; Research Center for Materials Science, Nagoya University, Nagoya, Aichi 464-8602, Japan. ; Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan. ; 1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Graduate School of Agriculture, Shizuoka University, 836 Ohya, Shizuoka 422-8529, Japan. ; Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan. ; 1] JST-CREST/Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan [2] JST-CREST/Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555, Japan. ; McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec H3A 2B4, Canada. ; Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada. ; 1] Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan [2] Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24784582" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Enzyme Activation ; Fibroblasts ; HeLa Cells ; Humans ; Membrane Potential, Mitochondrial ; Mice ; Mitochondria/metabolism ; Mutation/genetics ; Parkinson Disease ; Phosphorylation ; Phosphoserine/metabolism ; Protein Kinases/*metabolism ; Ubiquitin/chemistry/*metabolism ; Ubiquitin-Protein Ligases/genetics/*metabolism ; Ubiquitination
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
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    Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300 (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publikationsdatum: 1999-04-16
    Beschreibung: The cytokines LIF (leukemia inhibitory factor) and BMP2 (bone morphogenetic protein-2) signal through different receptors and transcription factors, namely STATs (signal transducers and activators of transcription) and Smads. LIF and BMP2 were found to act in synergy on primary fetal neural progenitor cells to induce astrocytes. The transcriptional coactivator p300 interacts physically with STAT3 at its amino terminus in a cytokine stimulation-independent manner, and with Smad1 at its carboxyl terminus in a cytokine stimulation-dependent manner. The formation of a complex between STAT3 and Smad1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neural progenitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakashima, K -- Yanagisawa, M -- Arakawa, H -- Kimura, N -- Hisatsune, T -- Kawabata, M -- Miyazono, K -- Taga, T -- New York, N.Y. -- Science. 1999 Apr 16;284(5413):479-82.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Cell Biology, Cell Fate Modulation Research Unit, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10205054" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Astrocytes/cytology ; Bone Morphogenetic Protein 2 ; Bone Morphogenetic Protein Receptors ; Bone Morphogenetic Proteins/metabolism/pharmacology ; COS Cells ; Cell Differentiation ; Cell Nucleus/metabolism ; Cells, Cultured ; Cytokines/*pharmacology ; DNA-Binding Proteins/*metabolism ; E1A-Associated p300 Protein ; Glial Fibrillary Acidic Protein/genetics ; Growth Inhibitors/metabolism/pharmacology ; *Interleukin-6 ; Leukemia Inhibitory Factor ; Leukemia Inhibitory Factor Receptor alpha Subunit ; Lymphokines/metabolism/pharmacology ; Mice ; Nuclear Proteins/*metabolism ; Promoter Regions, Genetic ; Receptors, Cell Surface/metabolism ; Receptors, Cytokine/metabolism ; *Receptors, Growth Factor ; Receptors, OSM-LIF ; STAT3 Transcription Factor ; Sequence Deletion ; *Signal Transduction ; Smad Proteins ; Smad1 Protein ; Stem Cells/cytology/metabolism ; Telencephalon/embryology/metabolism ; Trans-Activators/*metabolism ; *Transcriptional Activation ; *Transforming Growth Factor beta
    Print ISSN: 0036-8075
    Digitale ISSN: 1095-9203
    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von American Association for the Advancement of Science (AAAS)
    Standort Signatur Erwartet Verfügbarkeit
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  • 3
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    Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase (1997)
    American Association for the Advancement of Science (AAAS)
    Details
    Publikationsdatum: 1997-02-28
    Beschreibung: The small guanosine triphosphatase (GTPase) Rho is implicated in the formation of stress fibers and focal adhesions in fibroblasts stimulated by extracellular signals such as lysophosphatidic acid (LPA). Rho-kinase is activated by Rho and may mediate some biological effects of Rho. Microinjection of the catalytic domain of Rho-kinase into serum-starved Swiss 3T3 cells induced the formation of stress fibers and focal adhesions, whereas microinjection of the inactive catalytic domain, the Rho-binding domain, or the pleckstrin-homology domain inhibited the LPA-induced formation of stress fibers and focal adhesions. Thus, Rho-kinase appears to mediate signals from Rho and to induce the formation of stress fibers and focal adhesions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Amano, M -- Chihara, K -- Kimura, K -- Fukata, Y -- Nakamura, N -- Matsuura, Y -- Kaibuchi, K -- New York, N.Y. -- Science. 1997 Feb 28;275(5304):1308-11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Signal Transduction, Nara Institute of Science and Technology, Ikoma 630-01, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9036856" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): 3T3 Cells ; Actins/*metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; *Cell Adhesion ; Cell Line ; DNA, Complementary/genetics ; Enzyme Inhibitors/pharmacology ; GTP Phosphohydrolases/metabolism ; Intracellular Signaling Peptides and Proteins ; Lysophospholipids/pharmacology ; Mice ; Mutation ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism ; Recombinant Fusion Proteins/metabolism ; Staurosporine/pharmacology ; rho-Associated Kinases
    Print ISSN: 0036-8075
    Digitale ISSN: 1095-9203
    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von American Association for the Advancement of Science (AAAS)
    Standort Signatur Erwartet Verfügbarkeit
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  • 4
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    Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET (2010)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2010-02-19
    Beschreibung: Endogenous retroviruses (ERVs), retrovirus-like elements with long terminal repeats, are widely dispersed in the euchromatic compartment in mammalian cells, comprising approximately 10% of the mouse genome. These parasitic elements are responsible for 〉10% of spontaneous mutations. Whereas DNA methylation has an important role in proviral silencing in somatic and germ-lineage cells, an additional DNA-methylation-independent pathway also functions in embryonal carcinoma and embryonic stem (ES) cells to inhibit transcription of the exogenous gammaretrovirus murine leukaemia virus (MLV). Notably, a recent genome-wide study revealed that ERVs are also marked by histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3 in ES cells but not in mouse embryonic fibroblasts. However, the role that these marks have in proviral silencing remains unexplored. Here we show that the H3K9 methyltransferase ESET (also called SETDB1 or KMT1E) and the Kruppel-associated box (KRAB)-associated protein 1 (KAP1, also called TRIM28) are required for H3K9me3 and silencing of endogenous and introduced retroviruses specifically in mouse ES cells. Furthermore, whereas ESET enzymatic activity is crucial for HP1 binding and efficient proviral silencing, the H4K20 methyltransferases Suv420h1 and Suv420h2 are dispensable for silencing. Notably, in DNA methyltransferase triple knockout (Dnmt1(-/-)Dnmt3a(-/-)Dnmt3b(-/-)) mouse ES cells, ESET and KAP1 binding and ESET-mediated H3K9me3 are maintained and ERVs are minimally derepressed. We propose that a DNA-methylation-independent pathway involving KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Matsui, Toshiyuki -- Leung, Danny -- Miyashita, Hiroki -- Maksakova, Irina A -- Miyachi, Hitoshi -- Kimura, Hiroshi -- Tachibana, Makoto -- Lorincz, Matthew C -- Shinkai, Yoichi -- 77805/Canadian Institutes of Health Research/Canada -- 92090/Canadian Institutes of Health Research/Canada -- England -- Nature. 2010 Apr 8;464(7290):927-31. doi: 10.1038/nature08858. Epub 2010 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, 53 Shogoin, Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164836" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; Cell Line ; DNA (Cytosine-5-)-Methyltransferase/deficiency/genetics/metabolism ; DNA Methylation/genetics ; Embryonic Stem Cells/*enzymology/metabolism/*virology ; Endogenous Retroviruses/*genetics ; Fibroblasts ; Gene Deletion ; *Gene Silencing ; Histone-Lysine N-Methyltransferase/deficiency/genetics/*metabolism ; Mice ; Nuclear Proteins/metabolism ; Protein Methyltransferases/deficiency/genetics/*metabolism ; Proviruses/*genetics ; Repressor Proteins/metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 5
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    Nebulin and N-WASP cooperate to cause IGF-1-induced sarcomeric actin filament formation (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publikationsdatum: 2010-12-15
    Beschreibung: Insulin-like growth factor 1 (IGF-1) induces skeletal muscle maturation and enlargement (hypertrophy). These responses require protein synthesis and myofibril formation (myofibrillogenesis). However, the signaling mechanisms of myofibrillogenesis remain obscure. We found that IGF-1-induced phosphatidylinositol 3-kinase-Akt signaling formed a complex of nebulin and N-WASP at the Z bands of myofibrils by interfering with glycogen synthase kinase-3beta in mice. Although N-WASP is known to be an activator of the Arp2/3 complex to form branched actin filaments, the nebulin-N-WASP complex caused actin nucleation for unbranched actin filament formation from the Z bands without the Arp2/3 complex. Furthermore, N-WASP was required for IGF-1-induced muscle hypertrophy. These findings present the mechanisms of IGF-1-induced actin filament formation in myofibrillogenesis required for muscle maturation and hypertrophy and a mechanism of actin nucleation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Takano, Kazunori -- Watanabe-Takano, Haruko -- Suetsugu, Shiro -- Kurita, Souichi -- Tsujita, Kazuya -- Kimura, Sumiko -- Karatsu, Takashi -- Takenawa, Tadaomi -- Endo, Takeshi -- New York, N.Y. -- Science. 2010 Dec 10;330(6010):1536-40. doi: 10.1126/science.1197767.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Graduate School of Science, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21148390" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Actin Cytoskeleton/*metabolism ; Actins/*metabolism ; Animals ; COS Cells ; Cercopithecus aethiops ; Hypertrophy ; Insulin-Like Growth Factor I/*metabolism ; Mice ; Mice, Inbred ICR ; *Muscle Development ; Muscle Proteins/chemistry/*metabolism ; Muscle, Skeletal/metabolism/pathology ; Myofibrils/metabolism ; Phosphatidylinositol 3-Kinase/metabolism ; Protein Binding ; Protein Interaction Domains and Motifs ; Proto-Oncogene Proteins c-akt/metabolism ; RNA Interference ; Sarcomeres/*metabolism ; Signal Transduction ; Wiskott-Aldrich Syndrome Protein, Neuronal/chemistry/*metabolism ; src Homology Domains
    Print ISSN: 0036-8075
    Digitale ISSN: 1095-9203
    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von American Association for the Advancement of Science (AAAS)
    Standort Signatur Erwartet Verfügbarkeit
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  • 6
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    Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-kappaB activation (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publikationsdatum: 2014-05-17
    Beschreibung: A switchlike response in nuclear factor-kappaB (NF-kappaB) activity implies the existence of a threshold in the NF-kappaB signaling module. We show that the CARD-containing MAGUK protein 1 (CARMA1, also called CARD11)-TAK1 (MAP3K7)-inhibitor of NF-kappaB (IkappaB) kinase-beta (IKKbeta) module is a switch mechanism for NF-kappaB activation in B cell receptor (BCR) signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKKbeta to TAK1, generating a steep dose response to BCR stimulation. Mutation of the scaffolding protein CARMA1 at serine-578, an IKKbeta target, abrogated not only late TAK1 activity, but also the switchlike activation of NF-kappaB in single cells, suggesting that phosphorylation of this residue accounts for the feedback.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shinohara, Hisaaki -- Behar, Marcelo -- Inoue, Kentaro -- Hiroshima, Michio -- Yasuda, Tomoharu -- Nagashima, Takeshi -- Kimura, Shuhei -- Sanjo, Hideki -- Maeda, Shiori -- Yumoto, Noriko -- Ki, Sewon -- Akira, Shizuo -- Sako, Yasushi -- Hoffmann, Alexander -- Kurosaki, Tomohiro -- Okada-Hatakeyama, Mariko -- 5R01CA141722/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2014 May 16;344(6185):760-4. doi: 10.1126/science.1250020.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ; Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences (QC Bio) and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. ; Laboratory for Cell Signaling Dynamics, RIKEN Quantitative Biology Center (QBiC), 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan. Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan. ; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ; Graduate School of Engineering, Tottori University 4-101, Koyama-minami, Tottori 680-8552, Japan. ; Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. ; Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan. ; Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences (QC Bio) and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp. ; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp. ; Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24833394" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; B-Lymphocytes/metabolism ; CARD Signaling Adaptor Proteins/genetics/*metabolism ; Cell Line ; Chickens ; Feedback, Physiological ; Guanylate Cyclase/genetics/*metabolism ; I-kappa B Kinase/*metabolism ; MAP Kinase Kinase Kinases/genetics/*metabolism ; Mice ; Mice, Knockout ; Mutation ; NF-kappa B/*agonists ; Phosphorylation ; Receptors, Antigen, B-Cell/genetics/*metabolism ; Serine/genetics/metabolism ; Signal Transduction
    Print ISSN: 0036-8075
    Digitale ISSN: 1095-9203
    Thema: Biologie , Chemie und Pharmazie , Informatik , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von American Association for the Advancement of Science (AAAS)
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  • 7
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    Sema3A regulates bone-mass accrual through sensory innervations (2013)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2013-05-07
    Beschreibung: Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a(-/-) mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a(-/-) mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1(-/-) and Sema3aosx(-/-) mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin(-/-) and Sema3anestin(-/-) mice) had low bone mass, similar to Sema3a(-/-) mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin(-/-) mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin(-/-) mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a(-/-) mice, such as olfactory development, were identified in Sema3asynasin(-/-) mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a(-/-) mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fukuda, Toru -- Takeda, Shu -- Xu, Ren -- Ochi, Hiroki -- Sunamura, Satoko -- Sato, Tsuyoshi -- Shibata, Shinsuke -- Yoshida, Yutaka -- Gu, Zirong -- Kimura, Ayako -- Ma, Chengshan -- Xu, Cheng -- Bando, Waka -- Fujita, Koji -- Shinomiya, Kenichi -- Hirai, Takashi -- Asou, Yoshinori -- Enomoto, Mitsuhiro -- Okano, Hideyuki -- Okawa, Atsushi -- Itoh, Hiroshi -- NS065048/NS/NINDS NIH HHS/ -- England -- Nature. 2013 May 23;497(7450):490-3. doi: 10.1038/nature12115. Epub 2013 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, School of Medicine, Keio University, Shinanomachi 35, Shinjyuku-ku, Tokyo 160-8582, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23644455" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Animals ; *Bone Remodeling ; Bone and Bones/anatomy & histology/*innervation/*metabolism ; Cell Differentiation ; Cells, Cultured ; Female ; Male ; Mice ; Organ Size ; Osteoblasts/cytology/metabolism ; Semaphorin-3A/deficiency/genetics/*metabolism ; Sensory Receptor Cells/cytology/*metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
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  • 8
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    A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity (2013)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2013-11-01
    Beschreibung: Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-alpha pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-alpha pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okada-Iwabu, Miki -- Yamauchi, Toshimasa -- Iwabu, Masato -- Honma, Teruki -- Hamagami, Ken-ichi -- Matsuda, Koichi -- Yamaguchi, Mamiko -- Tanabe, Hiroaki -- Kimura-Someya, Tomomi -- Shirouzu, Mikako -- Ogata, Hitomi -- Tokuyama, Kumpei -- Ueki, Kohjiro -- Nagano, Tetsuo -- Tanaka, Akiko -- Yokoyama, Shigeyuki -- Kadowaki, Takashi -- England -- Nature. 2013 Nov 28;503(7477):493-9. doi: 10.1038/nature12656. Epub 2013 Oct 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan [3] Department of Molecular Medicinal Sciences on Metabolic Regulation, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24172895" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Adenylate Kinase/metabolism ; Adiponectin/metabolism/pharmacology ; Adipose Tissue, White/drug effects/metabolism/pathology ; Administration, Oral ; Animals ; Diabetes Mellitus, Type 2/complications/*drug therapy/metabolism/prevention & ; control ; Diet, High-Fat ; Drug Evaluation, Preclinical ; Dyslipidemias/drug therapy ; Enzyme Activation/drug effects ; Glucose Intolerance/drug therapy ; Inflammation/drug therapy ; Insulin Resistance ; Liver/drug effects/metabolism/pathology ; Longevity/*drug effects ; Mice ; Mitochondria/drug effects/metabolism ; Muscle Fibers, Skeletal/cytology/drug effects ; Muscles/cytology ; Obesity/complications/drug therapy/genetics/*physiopathology ; Oxidative Stress/drug effects ; PPAR alpha/metabolism ; Piperidines/administration & dosage/metabolism/*pharmacology/therapeutic use ; Receptors, Adiponectin/*agonists/deficiency/genetics/metabolism ; Signal Transduction/drug effects ; Small Molecule Libraries/chemistry ; Transcription Factors/biosynthesis ; Triglycerides/metabolism
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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    Statin treatment rescues FGFR3 skeletal dysplasia phenotypes (2014)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2014-09-19
    Beschreibung: Gain-of-function mutations in the fibroblast growth factor receptor 3 gene (FGFR3) result in skeletal dysplasias, such as thanatophoric dysplasia and achondroplasia (ACH). The lack of disease models using human cells has hampered the identification of a clinically effective treatment for these diseases. Here we show that statin treatment can rescue patient-specific induced pluripotent stem cell (iPSC) models and a mouse model of FGFR3 skeletal dysplasia. We converted fibroblasts from thanatophoric dysplasia type I (TD1) and ACH patients into iPSCs. The chondrogenic differentiation of TD1 iPSCs and ACH iPSCs resulted in the formation of degraded cartilage. We found that statins could correct the degraded cartilage in both chondrogenically differentiated TD1 and ACH iPSCs. Treatment of ACH model mice with statin led to a significant recovery of bone growth. These results suggest that statins could represent a medical treatment for infants and children with TD1 and ACH.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yamashita, Akihiro -- Morioka, Miho -- Kishi, Hiromi -- Kimura, Takeshi -- Yahara, Yasuhito -- Okada, Minoru -- Fujita, Kaori -- Sawai, Hideaki -- Ikegawa, Shiro -- Tsumaki, Noriyuki -- England -- Nature. 2014 Sep 25;513(7519):507-11. doi: 10.1038/nature13775. Epub 2014 Sep 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan. ; 1] Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2] Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. ; Department of Obstetrics and Gynecology, Hyogo College of Medicine, Hyogo 663-8501, Japan. ; Laboratory of Bone and Joint Diseases, Center for Integrated Medical Sciences, RIKEN, Tokyo 108-8639, Japan. ; 1] Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2] Japan Science and Technology Agency, CREST, Tokyo 102-0075, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25231866" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Achondroplasia/*drug therapy/genetics/*pathology ; Animals ; Bone Development/drug effects ; Cartilage/cytology/drug effects/pathology ; Cell Differentiation ; Chondrocytes/cytology/pathology ; Disease Models, Animal ; Female ; Fluorobenzenes/administration & dosage/pharmacology/therapeutic use ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & ; dosage/pharmacology/*therapeutic use ; Induced Pluripotent Stem Cells/cytology/pathology ; Lovastatin/pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Phenotype ; Pyrimidines/administration & dosage/pharmacology/therapeutic use ; Receptor, Fibroblast Growth Factor, Type 3/*deficiency/*genetics ; Rosuvastatin Calcium ; Sulfonamides/administration & dosage/pharmacology/therapeutic use ; Thanatophoric Dysplasia/*drug therapy/genetics/*pathology
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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  • 10
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    Meis1 regulates postnatal cardiomyocyte cell cycle arrest (2013)
    Nature Publishing Group (NPG)
    Details
    Publikationsdatum: 2013-04-19
    Beschreibung: The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by postnatal day 7 and the mechanisms of cardiomyocyte cell cycle arrest remain unclear. The homeodomain transcription factor Meis1 is required for normal cardiac development but its role in cardiomyocytes is unknown. Here we identify Meis1 as a critical regulator of the cardiomyocyte cell cycle. Meis1 deletion in mouse cardiomyocytes was sufficient for extension of the postnatal proliferative window of cardiomyocytes, and for re-activation of cardiomyocyte mitosis in the adult heart with no deleterious effect on cardiac function. In contrast, overexpression of Meis1 in cardiomyocytes decreased neonatal myocyte proliferation and inhibited neonatal heart regeneration. Finally, we show that Meis1 is required for transcriptional activation of the synergistic CDK inhibitors p15, p16 and p21. These results identify Meis1 as a critical transcriptional regulator of cardiomyocyte proliferation and a potential therapeutic target for heart regeneration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159712/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159712/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mahmoud, Ahmed I -- Kocabas, Fatih -- Muralidhar, Shalini A -- Kimura, Wataru -- Koura, Ahmed S -- Thet, Suwannee -- Porrello, Enzo R -- Sadek, Hesham A -- 1R01HL115275-01/HL/NHLBI NIH HHS/ -- R01 HL115275/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 May 9;497(7448):249-53. doi: 10.1038/nature12054. Epub 2013 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23594737" target="_blank"〉PubMed〈/a〉
    Schlagwort(e): Alleles ; Animals ; Animals, Newborn ; *Cell Cycle Checkpoints ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p15/metabolism ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Female ; Heart/anatomy & histology/physiology ; Homeodomain Proteins/genetics/*metabolism ; Male ; Mice ; Myocardial Infarction/metabolism/pathology ; Myocytes, Cardiac/*cytology/*metabolism ; Neoplasm Proteins/deficiency/genetics/*metabolism ; Regeneration ; Transcriptional Activation
    Print ISSN: 0028-0836
    Digitale ISSN: 1476-4687
    Thema: Biologie , Chemie und Pharmazie , Medizin , Allgemeine Naturwissenschaft , Physik
    Publiziert von Nature Publishing Group (NPG)
    Standort Signatur Erwartet Verfügbarkeit
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