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

Maofu Fu, Mahadev Rao, Toula Bouras, Chenguang Wang, Kongming Wu, Xueping Zhang, Zhiping Li, Tso Pang Yao, Richard G. Pestell

Research output: Contribution to journalArticle

203 Citations (Scopus)

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)γ-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 PPARγ function. Herein, murine embryonic fibroblast (MEF) differentiation by PPARγ 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 PPARγ-mediated adipogenesis. PPARγ activity was enhanced in cyclin D1-/- cells. Reintroduction of cyclin D1 inhibited basal and ligand-induced PPARγ activity and enhanced HDAC repression of PPARγ 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 PPARγ-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPARγ function.

Original languageEnglish
Pages (from-to)16934-16941
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number17
DOIs
Publication statusPublished - 29-04-2005

Fingerprint

Adipogenesis
Peroxisome Proliferator-Activated Receptors
Histone Deacetylases
Cyclin D1
Adipocytes
Response Elements
Histones
Retinoblastoma Binding Proteins
Chromatin
Histone Deacetylase 1
bcl-1 Genes
Ligands
Retinoblastoma Protein
Holoenzymes
Acetylation
Cyclin-Dependent Kinases
Lipoprotein Lipase
Chromatin Immunoprecipitation
Fibroblasts
Lysine

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Fu, Maofu ; Rao, Mahadev ; Bouras, Toula ; Wang, Chenguang ; Wu, Kongming ; Zhang, Xueping ; Li, Zhiping ; Yao, Tso Pang ; Pestell, Richard G. / Cyclin D1 inhibits peroxisome proliferator-activated receptor γ-mediated adipogenesis through histone deacetylase recruitment. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 17. pp. 16934-16941.
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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)γ-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 PPARγ function. Herein, murine embryonic fibroblast (MEF) differentiation by PPARγ 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 PPARγ-mediated adipogenesis. PPARγ activity was enhanced in cyclin D1-/- cells. Reintroduction of cyclin D1 inhibited basal and ligand-induced PPARγ activity and enhanced HDAC repression of PPARγ 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 PPARγ-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPARγ function.",
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Cyclin D1 inhibits peroxisome proliferator-activated receptor γ-mediated adipogenesis through histone deacetylase recruitment. / Fu, Maofu; Rao, Mahadev; Bouras, Toula; Wang, Chenguang; Wu, Kongming; Zhang, Xueping; Li, Zhiping; Yao, Tso Pang; Pestell, Richard G.

In: Journal of Biological Chemistry, Vol. 280, No. 17, 29.04.2005, p. 16934-16941.

Research output: Contribution to journalArticle

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AU - Fu, Maofu

AU - Rao, Mahadev

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AB - 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)γ-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 PPARγ function. Herein, murine embryonic fibroblast (MEF) differentiation by PPARγ 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 PPARγ-mediated adipogenesis. PPARγ activity was enhanced in cyclin D1-/- cells. Reintroduction of cyclin D1 inhibited basal and ligand-induced PPARγ activity and enhanced HDAC repression of PPARγ 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 PPARγ-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPARγ function.

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