Cyclin D1 Inhibits Peroxisome Proliferator-activated Receptor γ-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)␥-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␥ function. Herein, murine embryonic fibroblast (MEF) differentiation by PPAR␥ 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␥-mediated adipogenesis. PPAR␥ activity was enhanced in cyclin D1؊/؊ cells. Reintroduction of cyclin D1 inhibited basal and ligand-induced PPAR␥ activity and enhanced HDAC repression of PPAR␥ 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␥-mediated adipocyte differentiation through recruitment of HDACs to regulate PPAR response element local chromatin structure and PPAR␥ function.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). Cyclin D1 encodes a labile growth factor-inducible regulatory subunit of the holoenzyme that phosphorylates and inactivates the retinoblastoma protein (Rb).1 Cyclin D1 overexpression promotes G 1 phase progression in cultured cells and immunoneutralizing experiments have shown a requirement for cyclin D1 in fibroblast, mammary, and epithelial cell proliferation (3, 4). Furthermore, cyclin D1 overexpression was shown to induce mammary tumorigenesis and to collaborate with the c-myc oncogene to induce lymphomagenesis (6). Deletion of the cyclin D1 gene in mice has demonstrated a key role for cyclin D1 in several distinct processes, including retinal and mammary gland development (7), cellular migration (8), cellular proliferation and survival (9), angiogenesis (10), and adipocyte differentiation (5). Cyclin D1 Ϫ/Ϫ MEFs have enhanced adipocyte differentiation in response to PPAR␥ ligands, which is reversed by cyclin D1 reintroduction (5).In addition to promoting DNA synthesis and cellular proliferation, cyclin D1 has been shown to inhibit the activity o...

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