Cyclin D1 inhibits peroxisome proliferator-activated receptor γ-mediated adipogenesis through histone deacetylase recruitment

被引:228
作者
Fu, MF
Rao, M
Bouras, T
Wang, CG
Wu, KM
Zhang, XP
Li, ZP
Yao, TP
Pestell, RG
机构
[1] Georgetown Univ, Dept Oncol, Vincent T Lombardi Canc Res Ctr, Washington, DC 20057 USA
[2] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA
关键词
D O I
10.1074/jbc.M500403200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The cyclin D1 gene encodes the labile serum-inducible regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein. Overexpression of cyclin D1 promotes cellular proliferation and normal physiological levels of cyclin D1 function to inhibit adipocyte differentiation in vivo. We have previously shown that cyclin D1 inhibits peroxisome proliferator-activated receptor ( PPAR) gamma-dependent activity through a cyclin-dependent kinase- and retinoblastoma protein-binding-independent mechanism. In this study, we determined the molecular mechanism by which cyclin D1 regulated PPAR gamma function. Herein, murine embryonic fibroblast (MEF) differentiation by PPAR gamma ligand was associated with a reduction in histone deacetylase (HDAC1) activity. Cyclin D1(-/-) MEFs showed an increased propensity to undergo differentiation into adipocytes. Genetic deletion of cyclin D1 reduced HDAC1 activity. Reconstitution of cyclin D1 into the cyclin D1(-/-) MEFs increased HDAC1 activity and blocked PPAR gamma-mediated adipogenesis. PPAR gamma activity was enhanced in cyclin D1(-/-) cells. Reintroduction of cyclin D1 inhibited basal and ligand-induced PPAR gamma activity and enhanced HDAC repression of PPAR gamma activity. Cyclin D1 bound HDAC in vivo and preferentially physically associated with HDAC1, HDAC2, HDAC3, and HDAC5. Chromatin immunoprecipitation assay demonstrated that cyclin D1 enhanced recruitment of HDAC1 and HDAC3 and histone methyltransferase SUV39H1 to the PPAR response element of the lipoprotein lipase promoter and decreased acetylation of total histone H3 and histone H3 lysine 9. Collectively, these studies suggest an important role of cyclin D1 in regulation of PPAR gamma-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPAR gamma function.
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收藏
页码:16934 / 16941
页数:8
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