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Peroxisome Proliferator-Activated Receptor Recruits the Positive Transcription Elongation Factor b Complex to Activate Transcription and Promote Adipogenesis

Institut National de la Santé et de la Recherche Médicale (INSERM) (I.I., J.-S.A., C.C., D.S., L.F.), Unité 540, Equipe Avenir, Institut de Génetique Humaine (M.B.), and Centre Hospitalier Universitaire Arnaud de Villeneuve (L.F.), Montpellier F-34090, France; and Department of Biochemistry and Molecular Biology (R.K.P., J.B.H., I.K., K.K.), University of Southern Denmark, DK-5230 Odense M, Denmark

Address all correspondence and requests for reprints to: Lluis Fajas, Institut National de la Santé et de la Recherche Médicale, Equipe Avenir, Unité 540, 60 rue de Navacelles, Montpellier, France. E-mail: fajas{at}montp.inserm.fr.

Positive transcription elongation factor b (P-TEFb) phosphorylates the C-terminal domain of RNA polymerase II, facilitating transcriptional elongation. In addition to its participation in general transcription, P-TEFb is recruited to specific promoters by some transcription factors such as c-Myc or MyoD. The P-TEFb complex is composed of a cyclin-dependent kinase (cdk9) subunit and a regulatory partner (cyclin T1, cyclin T2, or cyclin K). Because cdk9 has been shown to participate in differentiation processes, such as muscle cell differentiation, we studied a possible role of cdk9 in adipogenesis. In this study we show that the expression of the cdk9 p55 isoform is highly regulated during 3T3-L1 adipocyte differentiation at RNA and protein levels. Furthermore, cdk9, as well as cyclin T1 and cyclin T2, shows differences in nuclear localization at distinct stages of adipogenesis. Overexpression of cdk9 increases the adipogenic potential of 3T3-L1 cells, whereas inhibition of cdk9 by specific cdk inhibitors, and dominant-negative cdk9 mutant impairs adipogenesis. We show that the positive effects of cdk9 on the differentiation of 3T3-L1 cells are mediated by a direct interaction with and phosphorylation of peroxisome proliferator-activated receptor (PPAR), which is the master regulator of this process, on the promoter of PPAR target genes. PPAR-cdk9 interaction results in increased transcriptional activity of PPAR and therefore increased adipogenesis.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARγ

Coregulators:   P-TEFb

Ligands:   GW 9662  |  Rosiglitazone

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