title: Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment.
abstract: 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 PPARgamma function. Herein, murine embryonic fibroblast (MEF) differentiation by PPARgamma 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 PPARgamma-mediated adipogenesis. PPARgamma activity was enhanced in cyclin D1-/- cells. Reintroduction of cyclin D1 inhibited basal and ligand-induced PPARgamma activity and enhanced HDAC repression of PPARgamma 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 PPARgamma-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPARgamma function.
authors.affiliation: Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington, D. C. 20057, USA.
authors.forename: Maofu
authors.initials: M
authors.lastname: Fu
authors.forename: Mahadev
authors.initials: M
authors.lastname: Rao
authors.forename: Toula
authors.initials: T
authors.lastname: Bouras
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Kongming
authors.initials: K
authors.lastname: Wu
authors.forename: Xueping
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019938:Cyclin D1 / Q000378:metabolism / Q000502:physiology*; D017353:Gene Deletion; D017930:Genes, Reporter; D005822:Genetic Vectors; D006655:Histone Deacetylases / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008071:Lipoprotein Lipase / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011496:Protein Methyltransferases; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012190:Retroviridae / Q000378:metabolism; D014162:Transfection
chemical_list: D001391:Azo Compounds; D002843:Chromatin; D006657:Histones; D047495:PPAR gamma; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D008156:Luciferases; C407843:SUV39H1 protein, human; C498700:Suv39h1 protein, mouse; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008071:Lipoprotein Lipase; D006655:Histone Deacetylases; C011049:oil red O