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  • Articles  (20)
  • Nature Publishing Group (NPG)  (20)
  • Chemistry and Pharmacology  (20)
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  • 1
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    Ubiquitin is phosphorylated by PINK1 to activate parkin (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-05-03
    Description: 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〉
    Keywords: 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
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  • 2
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    The Ectocarpus genome and the independent evolution of multicellularity in brown algae (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-06-04
    Description: Brown algae (Phaeophyceae) are complex photosynthetic organisms with a very different evolutionary history to green plants, to which they are only distantly related. These seaweeds are the dominant species in rocky coastal ecosystems and they exhibit many interesting adaptations to these, often harsh, environments. Brown algae are also one of only a small number of eukaryotic lineages that have evolved complex multicellularity (Fig. 1). We report the 214 million base pair (Mbp) genome sequence of the filamentous seaweed Ectocarpus siliculosus (Dillwyn) Lyngbye, a model organism for brown algae, closely related to the kelps (Fig. 1). Genome features such as the presence of an extended set of light-harvesting and pigment biosynthesis genes and new metabolic processes such as halide metabolism help explain the ability of this organism to cope with the highly variable tidal environment. The evolution of multicellularity in this lineage is correlated with the presence of a rich array of signal transduction genes. Of particular interest is the presence of a family of receptor kinases, as the independent evolution of related molecules has been linked with the emergence of multicellularity in both the animal and green plant lineages. The Ectocarpus genome sequence represents an important step towards developing this organism as a model species, providing the possibility to combine genomic and genetic approaches to explore these and other aspects of brown algal biology further.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cock, J Mark -- Sterck, Lieven -- Rouze, Pierre -- Scornet, Delphine -- Allen, Andrew E -- Amoutzias, Grigoris -- Anthouard, Veronique -- Artiguenave, Francois -- Aury, Jean-Marc -- Badger, Jonathan H -- Beszteri, Bank -- Billiau, Kenny -- Bonnet, Eric -- Bothwell, John H -- Bowler, Chris -- Boyen, Catherine -- Brownlee, Colin -- Carrano, Carl J -- Charrier, Benedicte -- Cho, Ga Youn -- Coelho, Susana M -- Collen, Jonas -- Corre, Erwan -- Da Silva, Corinne -- Delage, Ludovic -- Delaroque, Nicolas -- Dittami, Simon M -- Doulbeau, Sylvie -- Elias, Marek -- Farnham, Garry -- Gachon, Claire M M -- Gschloessl, Bernhard -- Heesch, Svenja -- Jabbari, Kamel -- Jubin, Claire -- Kawai, Hiroshi -- Kimura, Kei -- Kloareg, Bernard -- Kupper, Frithjof C -- Lang, Daniel -- Le Bail, Aude -- Leblanc, Catherine -- Lerouge, Patrice -- Lohr, Martin -- Lopez, Pascal J -- Martens, Cindy -- Maumus, Florian -- Michel, Gurvan -- Miranda-Saavedra, Diego -- Morales, Julia -- Moreau, Herve -- Motomura, Taizo -- Nagasato, Chikako -- Napoli, Carolyn A -- Nelson, David R -- Nyvall-Collen, Pi -- Peters, Akira F -- Pommier, Cyril -- Potin, Philippe -- Poulain, Julie -- Quesneville, Hadi -- Read, Betsy -- Rensing, Stefan A -- Ritter, Andres -- Rousvoal, Sylvie -- Samanta, Manoj -- Samson, Gaelle -- Schroeder, Declan C -- Segurens, Beatrice -- Strittmatter, Martina -- Tonon, Thierry -- Tregear, James W -- Valentin, Klaus -- von Dassow, Peter -- Yamagishi, Takahiro -- Van de Peer, Yves -- Wincker, Patrick -- England -- Nature. 2010 Jun 3;465(7298):617-21. doi: 10.1038/nature09016.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉UPMC Universite Paris 6, The Marine Plants and Biomolecules Laboratory, UMR 7139, Station Biologique de Roscoff, Place Georges Teissier, BP74, 29682 Roscoff Cedex, France. cock@sb-roscoff.fr〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20520714" target="_blank"〉PubMed〈/a〉
    Keywords: Algal Proteins/*genetics ; Animals ; *Biological Evolution ; Eukaryota ; Evolution, Molecular ; Genome/*genetics ; Molecular Sequence Data ; Phaeophyta/*cytology/*genetics/metabolism ; Phylogeny ; Pigments, Biological/biosynthesis ; Signal Transduction/genetics
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  • 3
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    Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-02-19
    Description: 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〉
    Keywords: 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
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  • 4
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    Giant magneto-elastic coupling in multiferroic hexagonal manganites (2008)
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    Publication Date: 2008-02-15
    Description: The motion of atoms in a solid always responds to cooling or heating in a way that is consistent with the symmetry of the given space group of the solid to which they belong. When the atoms move, the electronic structure of the solid changes, leading to different physical properties. Therefore, the determination of where atoms are and what atoms do is a cornerstone of modern solid-state physics. However, experimental observations of atomic displacements measured as a function of temperature are very rare, because those displacements are, in almost all cases, exceedingly small. Here we show, using a combination of diffraction techniques, that the hexagonal manganites RMnO3 (where R is a rare-earth element) undergo an isostructural transition with exceptionally large atomic displacements: two orders of magnitude larger than those seen in any other magnetic material, resulting in an unusually strong magneto-elastic coupling. We follow the exact atomic displacements of all the atoms in the unit cell as a function of temperature and find consistency with theoretical predictions based on group theories. We argue that this gigantic magneto-elastic coupling in RMnO3 holds the key to the recently observed magneto-electric phenomenon in this intriguing class of materials.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Seongsu -- Pirogov, A -- Kang, Misun -- Jang, Kwang-Hyun -- Yonemura, M -- Kamiyama, T -- Cheong, S-W -- Gozzo, F -- Shin, Namsoo -- Kimura, H -- Noda, Y -- Park, J-G -- England -- Nature. 2008 Feb 14;451(7180):805-8. doi: 10.1038/nature06507.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics, SungKyunKwan University, Suwon 440-746, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18273014" target="_blank"〉PubMed〈/a〉
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  • 5
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    Structural basis for translational fidelity ensured by transfer RNA lysidine synthetase (2009)
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    Publication Date: 2009-10-23
    Description: Maturation of precursor transfer RNA (pre-tRNA) includes excision of the 5' leader and 3' trailer sequences, removal of introns and addition of the CCA terminus. Nucleotide modifications are incorporated at different stages of tRNA processing, after the RNA molecule adopts the proper conformation. In bacteria, tRNA(Ile2) lysidine synthetase (TilS) modifies cytidine into lysidine (L; 2-lysyl-cytidine) at the first anticodon of tRNA(Ile2) (refs 4-9). This modification switches tRNA(Ile2) from a methionine-specific to an isoleucine-specific tRNA. However, the aminoacylation of tRNA(Ile2) by methionyl-tRNA synthetase (MetRS), before the modification by TilS, might lead to the misincorporation of methionine in response to isoleucine codons. The mechanism used by bacteria to avoid this pitfall is unknown. Here we show that the TilS enzyme specifically recognizes and modifies tRNA(Ile2) in its precursor form, thereby avoiding translation errors. We identified the lysidine modification in pre-tRNA(Ile2) isolated from RNase-E-deficient Escherichia coli and did not detect mature tRNA(Ile2) lacking this modification. Our kinetic analyses revealed that TilS can modify both types of RNA molecule with comparable efficiencies. X-ray crystallography and mutational analyses revealed that TilS specifically recognizes the entire L-shape structure in pre-tRNA(Ile2) through extensive interactions coupled with sequential domain movements. Our results demonstrate how TilS prevents the recognition of tRNA(Ile2) by MetRS and achieves high specificity for its substrate. These two key points form the basis for maintaining the fidelity of isoleucine codon translation in bacteria. Our findings also provide a rationale for the necessity of incorporating specific modifications at the precursor level during tRNA biogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakanishi, Kotaro -- Bonnefond, Luc -- Kimura, Satoshi -- Suzuki, Tsutomu -- Ishitani, Ryuichiro -- Nureki, Osamu -- England -- Nature. 2009 Oct 22;461(7267):1144-8. doi: 10.1038/nature08474.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa 225-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847269" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acyl-tRNA Synthetases/*chemistry/genetics/*metabolism ; Apoproteins/genetics/metabolism ; Bacillus subtilis ; Bacterial Proteins/*chemistry/genetics/*metabolism ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; Escherichia coli ; Geobacillus ; Kinetics ; Lysine/analogs & derivatives/metabolism ; Mass Spectrometry ; Models, Molecular ; Molecular Sequence Data ; *Protein Biosynthesis ; Pyrimidine Nucleosides/metabolism ; RNA, Transfer, Ile/genetics/metabolism ; Substrate Specificity
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  • 6
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    Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-13
    Description: The mucosal immune system forms the largest part of the entire immune system, containing about three-quarters of all lymphocytes and producing grams of secretory IgA daily to protect the mucosal surface from pathogens. To evoke the mucosal immune response, antigens on the mucosal surface must be transported across the epithelial barrier into organized lymphoid structures such as Peyer's patches. This function, called antigen transcytosis, is mediated by specialized epithelial M cells. The molecular mechanisms promoting this antigen uptake, however, are largely unknown. Here we report that glycoprotein 2 (GP2), specifically expressed on the apical plasma membrane of M cells among enterocytes, serves as a transcytotic receptor for mucosal antigens. Recombinant GP2 protein selectively bound a subset of commensal and pathogenic enterobacteria, including Escherichia coli and Salmonella enterica serovar Typhimurium (S. Typhimurium), by recognizing FimH, a component of type I pili on the bacterial outer membrane. Consistently, these bacteria were colocalized with endogenous GP2 on the apical plasma membrane as well as in cytoplasmic vesicles in M cells. Moreover, deficiency of bacterial FimH or host GP2 led to defects in transcytosis of type-I-piliated bacteria through M cells, resulting in an attenuation of antigen-specific immune responses in Peyer's patches. GP2 is therefore a previously unrecognized transcytotic receptor on M cells for type-I-piliated bacteria and is a prerequisite for the mucosal immune response to these bacteria. Given that M cells are considered a promising target for oral vaccination against various infectious diseases, the GP2-dependent transcytotic pathway could provide a new target for the development of M-cell-targeted mucosal vaccines.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hase, Koji -- Kawano, Kazuya -- Nochi, Tomonori -- Pontes, Gemilson Soares -- Fukuda, Shinji -- Ebisawa, Masashi -- Kadokura, Kazunori -- Tobe, Toru -- Fujimura, Yumiko -- Kawano, Sayaka -- Yabashi, Atsuko -- Waguri, Satoshi -- Nakato, Gaku -- Kimura, Shunsuke -- Murakami, Takaya -- Iimura, Mitsutoshi -- Hamura, Kimiyo -- Fukuoka, Shin-Ichi -- Lowe, Anson W -- Itoh, Kikuji -- Kiyono, Hiroshi -- Ohno, Hiroshi -- DK43294/DK/NIDDK NIH HHS/ -- DK56339/DK/NIDDK NIH HHS/ -- England -- Nature. 2009 Nov 12;462(7270):226-30. doi: 10.1038/nature08529.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Epithelial Immunobiology, Research Center for Allergy and Immunology, RIKEN, Kanagawa 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19907495" target="_blank"〉PubMed〈/a〉
    Keywords: Adhesins, Escherichia coli/genetics/immunology/*metabolism ; Animals ; Antigens, Bacterial/genetics/immunology/*metabolism ; Cell Line ; Epithelial Cells/*immunology/metabolism ; Escherichia coli/immunology/metabolism ; Fimbriae Proteins/genetics/immunology/*metabolism ; GPI-Linked Proteins ; Glycoproteins ; HeLa Cells ; Humans ; Immunity, Mucosal/*immunology ; Intestines/cytology ; Membrane Glycoproteins/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Peyer's Patches/*cytology/immunology ; Salmonella typhimurium/genetics/immunology/metabolism ; Substrate Specificity
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  • 7
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    Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-06-23
    Description: Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts, mediated primarily by proliferation of pre-existing cardiomyocytes. However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1alpha) subunit is critical for their maintenance and function. Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1alpha is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific alpha myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kimura, Wataru -- Xiao, Feng -- Canseco, Diana C -- Muralidhar, Shalini -- Thet, SuWannee -- Zhang, Helen M -- Abderrahman, Yezan -- Chen, Rui -- Garcia, Joseph A -- Shelton, John M -- Richardson, James A -- Ashour, Abdelrahman M -- Asaithamby, Aroumougame -- Liang, Hanquan -- Xing, Chao -- Lu, Zhigang -- Zhang, Cheng Cheng -- Sadek, Hesham A -- I01 BX000446/BX/BLRD VA/ -- R01 HL108104/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Jul 9;523(7559):226-30. doi: 10.1038/nature14582. Epub 2015 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan. ; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Departments of Physiology and Developmental Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Medicine, VA North Texas Health Care System, 4600 South Lancaster Road, Dallas, Texas 75216, USA. ; 1] Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Hamon Center for Regenerative Science and Medicine, 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/26098368" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Hypoxia ; Cell Proliferation/genetics ; Female ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Male ; Mice ; Mice, Transgenic ; Myocardium/*cytology ; Myocytes, Cardiac/*cytology/metabolism ; Protein Structure, Tertiary ; Recombinant Fusion Proteins/genetics/*metabolism ; Recombinases/genetics/metabolism ; Signal Transduction ; Stem Cells/cytology/metabolism
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  • 8
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    Sema3A regulates bone-mass accrual through sensory innervations (2013)
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    Publication Date: 2013-05-07
    Description: 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〉
    Keywords: 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
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-01
    Description: 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〉
    Keywords: 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
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
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    Statin treatment rescues FGFR3 skeletal dysplasia phenotypes (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-09-19
    Description: 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〉
    Keywords: 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
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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