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  • 1
    Online Resource
    Online Resource
    TGF-β/Smad3 Signals Repress Chondrocyte Hypertrophic Differentiation and Are Required for Maintaining Articular Cartilage
    Rockefeller University Press ; 2001
    In:  The Journal of Cell Biology Vol. 153, No. 1 ( 2001-04-02), p. 35-46
    Details
    In: The Journal of Cell Biology, Rockefeller University Press, Vol. 153, No. 1 ( 2001-04-02), p. 35-46
    Abstract: Endochondral ossification begins from the condensation and differentiation of mesenchymal cells into cartilage. The cartilage then goes through a program of cell proliferation, hypertrophic differentiation, calcification, apoptosis, and eventually is replaced by bone. Unlike most cartilage, articular cartilage is arrested before terminal hypertrophic differentiation. In this study, we showed that TGF-β/Smad3 signals inhibit terminal hypertrophic differentiation of chondrocyte and are essential for maintaining articular cartilage. Mutant mice homozygous for a targeted disruption of Smad3 exon 8 (Smad3ex8/ex8) developed degenerative joint disease resembling human osteoarthritis, as characterized by progressive loss of articular cartilage, formation of large osteophytes, decreased production of proteoglycans, and abnormally increased number of type X collagen–expressing chondrocytes in synovial joints. Enhanced terminal differentiation of epiphyseal growth plate chondrocytes was also observed in mutant mice shortly after weaning. In an in vitro embryonic metatarsal rudiment culture system, we found that TGF-β1 significantly inhibits chondrocyte differentiation of wild-type metatarsal rudiments. However, this inhibition is diminished in metatarsal bones isolated from Smad3ex8/ex8 mice. These data suggest that TGF-β/Smad3 signals are essential for repressing articular chondrocyte differentiation. Without these inhibition signals, chondrocytes break quiescent state and undergo abnormal terminal differentiation, ultimately leading to osteoarthritis.
    Type of Medium: Online Resource
    ISSN: 0021-9525 , 1540-8140
    URL: Article
    DOI: 10.1083/jcb.153.1.35
    RVK:
    WA 15000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2001
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    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Tumorigenesis as a consequence of genetic instability in Brca1 mutant mice
    Elsevier BV ; 2001
    In:  Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis Vol. 477, No. 1-2 ( 2001-6), p. 183-189
    Details
    In: Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Elsevier BV, Vol. 477, No. 1-2 ( 2001-6), p. 183-189
    Type of Medium: Online Resource
    ISSN: 0027-5107
    URL: Article
    DOI: 10.1016/S0027-5107(01)00119-1
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2001
    detail.hit.zdb_id: 1491099-8
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 38 ( 2008-09-23), p. 14447-14452
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 38 ( 2008-09-23), p. 14447-14452
    Abstract: Here, we demonstrate a role for the mitochondrial NAD-dependent deacetylase Sirt3 in the maintenance of basal ATP levels and as a regulator of mitochondrial electron transport. We note that Sirt3 −/− mouse embryonic fibroblasts have a reduction in basal ATP levels. Reconstitution with wild-type but not a deacetylase-deficient form of Sirt3 restored ATP levels in these cells. Furthermore in wild-type mice, the resting level of ATP correlates with organ-specific Sirt3 protein expression. Remarkably, in mice lacking Sirt3, basal levels of ATP in the heart, kidney, and liver were reduced 〉 50%. We further demonstrate that mitochondrial protein acetylation is markedly elevated in Sirt3 −/− tissues. In addition, in the absence of Sirt3, multiple components of Complex I of the electron transport chain demonstrate increased acetylation. Sirt3 can also physically interact with at least one of the known subunits of Complex I, the 39-kDa protein NDUFA9. Functional studies demonstrate that mitochondria from Sirt3 −/− animals display a selective inhibition of Complex I activity. Furthermore, incubation of exogenous Sirt3 with mitochondria can augment Complex I activity. These results implicate protein acetylation as an important regulator of Complex I activity and demonstrate that Sirt3 functions in vivo to regulate and maintain basal ATP levels.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0803790105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 50 ( 2010-12-14), p. 21790-21794
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 50 ( 2010-12-14), p. 21790-21794
    Abstract: In yeast, Sir2 family proteins (sirtuins) regulate gene silencing, recombination, DNA repair, and aging via histone deacetylation. Most of the seven mammalian sirtuins (Sirt1–Sirt7) have been implicated as NAD + -dependent protein deacetylases with targets ranging from transcriptional regulators to metabolic enzymes. We report that neural-specific deletion of sirtuin 6 (Sirt6) in mice leads to postnatal growth retardation due to somatotropic attenuation through low growth hormone (GH) and insulin-like growth factor 1 (IGF1) levels. However, unlike Sirt6 null mice, neural Sirt6-deleted mice do not die from hypoglycemia. Instead, over time, neural Sirt6-deleted mice reach normal size and ultimately become obese. Molecularly, Sirt6 deletion results in striking hyperacetylation of histone H3 lysine 9 (H3K9) and lysine 56 (H3K56), two chromatin marks implicated in the regulation of gene activity and chromatin structure, in various brain regions including those involved in neuroendocrine regulation. On the basis of these findings, we propose that Sirt6 functions as a central regulator of somatic growth and plays an important role in preventing obesity by modulating neural chromatin structure and gene activity.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1016306107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 29 ( 2014-07-22), p. 10684-10689
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 29 ( 2014-07-22), p. 10684-10689
    Abstract: In mammalian cells, tumor suppressor p53 plays critical roles in the regulation of glucose metabolism, including glycolysis and oxidative phosphorylation, but whether and how p53 also regulates gluconeogenesis is less clear. Here, we report that p53 efficiently down-regulates the expression of phosphoenolpyruvate carboxykinase ( PCK1 ) and glucose-6-phosphatase ( G6PC ), which encode rate-limiting enzymes in gluconeogenesis. Cell-based assays demonstrate the p53-dependent nuclear exclusion of forkhead box protein O1 (FoxO1), a key transcription factor that mediates activation of PCK1 and G6PC , with consequent alleviation of FoxO1-dependent gluconeogenesis. Further mechanistic studies show that p53 directly activates expression of the NAD + -dependent histone deacetylase sirtuin 6 (SIRT6), whose interaction with FoxO1 leads to FoxO1 deacetylation and export to the cytoplasm. In support of these observations, p53-mediated FoxO1 nuclear exclusion, down-regulation of PCK1 and G6PC expression, and regulation of glucose levels were confirmed in C57BL/J6 mice and in liver-specific Sirt6 conditional knockout mice. Our results provide insights into mechanisms of metabolism-related p53 functions that may be relevant to tumor suppression.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1411026111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Cholinergic dilation of cerebral blood vessels is abolished in M 5 muscarinic acetylcholine receptor knockout mice
    Proceedings of the National Academy of Sciences ; 2001
    In:  Proceedings of the National Academy of Sciences Vol. 98, No. 24 ( 2001-11-20), p. 14096-14101
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 24 ( 2001-11-20), p. 14096-14101
    Abstract: The M 5 muscarinic receptor is the most recent member of the muscarinic acetylcholine receptor family (M 1 -M 5 ) to be cloned. At present, the physiological relevance of this receptor subtype remains unknown, primarily because of its low expression levels and the lack of M 5 receptor-selective ligands. To circumvent these difficulties, we used gene targeting technology to generate M 5 receptor-deficient mice ( M5R −/− mice). M5R −/− mice did not differ from their wild-type littermates in various behavioral and pharmacologic tests. However, in vitro neurotransmitter release experiments showed that M 5 receptors play a role in facilitating muscarinic agonist-induced dopamine release in the striatum. Because M 5 receptor mRNA has been detected in several blood vessels, we also investigated whether the lack of M 5 receptors led to changes in vascular tone by using several in vivo and in vitro vascular preparations. Strikingly, acetylcholine, a powerful dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5R −/− mice. This effect was specific for cerebral blood vessels, because acetylcholine-mediated dilation of extra-cerebral arteries remained fully intact in M5R −/− mice. Our findings provide direct evidence that M 5 muscarinic receptors are physiologically relevant. Because it has been suggested that impaired cholinergic dilation of cerebral blood vessels may play a role in the pathophysiology of Alzheimer's disease and focal cerebral ischemia, cerebrovascular M 5 receptors may represent an attractive therapeutic target.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.251542998
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2001
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Smad4 is critical for self-renewal of hematopoietic stem cells
    Rockefeller University Press ; 2007
    In:  The Journal of Cell Biology Vol. 176, No. 7 ( 2007-03-26), p. i13-i13
    Details
    In: The Journal of Cell Biology, Rockefeller University Press, Vol. 176, No. 7 ( 2007-03-26), p. i13-i13
    Type of Medium: Online Resource
    ISSN: 0021-9525 , 1540-8140
    URL: Article
    DOI: 10.1083/JCB1767OIA13
    RVK:
    WA 15000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2007
    detail.hit.zdb_id: 1421310-2
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Disruption of Transforming Growth Factor-β Signaling in ELF β-Spectrin-Deficient Mice
    American Association for the Advancement of Science (AAAS) ; 2003
    In:  Science Vol. 299, No. 5606 ( 2003-01-24), p. 574-577
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 299, No. 5606 ( 2003-01-24), p. 574-577
    Abstract: Disruption of the adaptor protein ELF, a β-spectrin, leads to disruption of transforming growth factor–β (TGF-β) signaling by Smad proteins in mice. Elf −/− mice exhibit a phenotype similar to smad2 +/− / smad3 +/− mutant mice of midgestational death due to gastrointestinal, liver, neural, and heart defects. We show that TGF-β triggers phosphorylation and association of ELF with Smad3 and Smad4, followed by nuclear translocation. ELF deficiency results in mislocalization of Smad3 and Smad4 and loss of the TGF-β–dependent transcriptional response, which could be rescued by overexpression of the COOH-terminal region of ELF. This study reveals an unexpected molecular link between a major dynamic scaffolding protein and a key signaling pathway.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1075994
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2003
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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  • 9
    Online Resource
    Online Resource
    BRCA1-associated tumorigenesis: what have we learned from knockout mice?
    Elsevier BV ; 2001
    In:  Trends in Genetics Vol. 17, No. 10 ( 2001-10), p. S18-S22
    Details
    In: Trends in Genetics, Elsevier BV, Vol. 17, No. 10 ( 2001-10), p. S18-S22
    Type of Medium: Online Resource
    ISSN: 0168-9525
    URL: Article
    DOI: 10.1016/S0168-9525(01)02451-9
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2001
    detail.hit.zdb_id: 2010993-3
    SSG: 12
    SSG: 15,3
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  • 10
    Online Resource
    Online Resource
    A requirement for breast-cancer-associated gene 1 (BRCA1) in the spindle checkpoint
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 49 ( 2004-12-07), p. 17108-17113
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 49 ( 2004-12-07), p. 17108-17113
    Abstract: BRCA1-associated breast cancer exhibits significantly higher levels of chromosomal abnormalities than sporadic breast cancers. However, the molecular mechanisms regarding the roles of BRCA1 in maintaining genome integrity remain elusive. By using a mouse model deficient for Brca1 full-length isoform ( Brca1 Δ 11/ Δ 11 ), we found that Brca1 Δ 11/ Δ 11 cells displayed decreased expression of a number of genes that are involved in the spindle checkpoint, including Mad2, which is a key component of spindle checkpoint that inhibits anaphase-promoting complex. We showed that Brca1 Δ 11/ Δ 11 cells failed to arrest at metaphase in the presence of nocodazole and underwent apoptosis because of activation of p53. Consistently, reconstitution of Mad2 in Brca1 Δ 11/ Δ 11 cells partially restored the spindle checkpoint and attenuated apoptosis. By using UBR60 cells, which carry tetracycline-regulated expression of BRCA1, we demonstrated that BRCA1 binds to transcription factor OCT-1 and up-regulates the transcription of MAD2. Furthermore, we showed that the induction of BRCA1 to endogenous MAD2 or transfected MAD2 luciferase reporter in UBR60 cells was completely inhibited by acute suppression of BRCA1 by RNA interference. These data reveal a role of BRCA1 in maintaining genome integrity by interplaying with p53 and genes that are involved in the spindle checkpoint and apoptosis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0407585101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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