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

Publication ,  Journal Article
Fu, M; Rao, M; Bouras, T; Wang, C; Wu, K; Zhang, X; Li, Z; Yao, T-P; Pestell, RG
Published in: J Biol Chem
April 29, 2005

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.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 29, 2005

Volume

280

Issue

17

Start / End Page

16934 / 16941

Location

United States

Related Subject Headings

  • Transfection
  • Retroviridae
  • Retinoblastoma Protein
  • Repressor Proteins
  • Protein Structure, Tertiary
  • Protein Methyltransferases
  • Protein Binding
  • Promoter Regions, Genetic
  • Phosphorylation
  • PPAR gamma
 

Citation

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Fu, M., Rao, M., Bouras, T., Wang, C., Wu, K., Zhang, X., … Pestell, R. G. (2005). Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment. J Biol Chem, 280(17), 16934–16941. https://doi.org/10.1074/jbc.M500403200
Fu, Maofu, Mahadev Rao, Toula Bouras, Chenguang Wang, Kongming Wu, Xueping Zhang, Zhiping Li, Tso-Pang Yao, and Richard G. Pestell. “Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment.J Biol Chem 280, no. 17 (April 29, 2005): 16934–41. https://doi.org/10.1074/jbc.M500403200.
Fu M, Rao M, Bouras T, Wang C, Wu K, Zhang X, et al. Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment. J Biol Chem. 2005 Apr 29;280(17):16934–41.
Fu, Maofu, et al. “Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment.J Biol Chem, vol. 280, no. 17, Apr. 2005, pp. 16934–41. Pubmed, doi:10.1074/jbc.M500403200.
Fu M, Rao M, Bouras T, Wang C, Wu K, Zhang X, Li Z, Yao T-P, Pestell RG. Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment. J Biol Chem. 2005 Apr 29;280(17):16934–16941.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

April 29, 2005

Volume

280

Issue

17

Start / End Page

16934 / 16941

Location

United States

Related Subject Headings

  • Transfection
  • Retroviridae
  • Retinoblastoma Protein
  • Repressor Proteins
  • Protein Structure, Tertiary
  • Protein Methyltransferases
  • Protein Binding
  • Promoter Regions, Genetic
  • Phosphorylation
  • PPAR gamma