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The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation.
The retinoblastoma protein (RB) has previously been shown to facilitate adipocyte differentiation by inducing cell cycle arrest and enhancing the transactivation by the adipogenic CCAAT/enhancer binding proteins (C/EBP). We show here that the peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor pivotal for adipogenesis, promotes adipocyte differentiation more efficiently in the absence of RB. PPARgamma and RB were shown to coimmunoprecipitate, and this PPARgamma-RB complex also contains the histone deacetylase HDAC3, thereby attenuating PPARgamma's capacity to drive gene expression and adipocyte differentiation. Dissociation of the PPARgamma-RB-HDAC3 complex by RB phosphorylation or by inhibition of HDAC activity stimulates adipocyte differentiation. These observations underscore an important function of both RB and HDAC3 in fine-tuning PPARgamma activity and adipocyte differentiation.
3T3 Cells, Adipocytes/cytology, Adipocytes/drug effects, Animals, Cell Differentiation/drug effects, Cell Differentiation/physiology, Gene Expression Regulation, Enzymologic/drug effects, Gene Expression Regulation, Enzymologic/genetics, Genes, Reporter/genetics, Histone Deacetylases/metabolism, Lipoprotein Lipase/genetics, Lipoprotein Lipase/metabolism, Macromolecular Substances, Mice, Phosphorylation, Protein Binding/drug effects, Protein Binding/genetics, Protein Structure, Tertiary/genetics, RNA, Messenger/metabolism, Receptors, Cytoplasmic and Nuclear/metabolism, Recombinant Fusion Proteins/diagnostic use, Retinoblastoma Protein/deficiency, Retinoblastoma Protein/genetics, Signal Transduction/drug effects, Signal Transduction/genetics, Stem Cells/cytology, Stem Cells/drug effects, Thiazoles/pharmacology, Thiazolidinediones, Transcription Factors/metabolism
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