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.
Highlights
The cyclin D1 gene was cloned as a breakpoint rearrangement in parathyroid adenoma [1] and as a macrophage colonystimulating factor-1-responsive gene in the mouse [2]
We assessed the role of cyclin D1 in regulating cellular HDAC activity during adipocyte differentiation of murine embryonic fibroblast (MEF)
MEFs derived from either cyclin D1 wild type or cyclin D1Ϫ/Ϫ mice were treated with differentiation medium and troglitazone, a peroxisome proliferator-activated receptor (PPAR)␥ agonist, as described previously [5]
Summary
Retinoblastoma protein; MEF, murine embryonic fibroblast; Cdk, cyclin-dependent kinase; PPAR, peroxisome proliferator-activated receptor; PPARE, PPAR␥ response element; GFP, green fluorescent protein; ChIP, chromatin immunoprecipitation; LPL, lipoprotein lipase; MSCV, murine stem cell virus; IRES, internal ribosome entry segment. This paper is available on line at http://www.jbc.org the potential role of cyclin D1 in regulating HDAC activity and adipocyte differentiation. Detailed analyses demonstrated that cyclin D1 induces HDAC activity and blocks adipocyte differentiation. Cyclin D1 physically associates with HDACs and inhibits basal and ligand-induced PPAR␥ activity through recruitment of HDACs and histone methyltransferase to the PPAR␥ response element (PPARE) of the lipoprotein lipase (LPL) promoter
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