Peroxisome proliferator-activated receptor gamma recruits the positive transcription elongation factor b complex to activate transcription and promote adipogenesis.
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 gamma (PPARgamma), which is the master regulator of this process, on the promoter of PPARgamma target genes. PPARgamma-cdk9 interaction results in increased transcriptional activity of PPARgamma and therefore increased adipogenesis.
Institut National de la Santé et de la Recherche Médicale, Equipe Avenir, Unité 540, 60 rue de Navacelles, Montpellier, France.
Irena
I
Iankova
Rasmus K
RK
Petersen
Jean-Sébastien
JS
Annicotte
Carine
C
Chavey
Jacob B
JB
Hansen
Irina
I
Kratchmarova
David
D
Sarruf
Monsef
M
Benkirane
Karsten
K
Kristiansen
Lluis
L
Fajas
D016475:3T3 Cells; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D005786:Gene Expression Regulation; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011485:Protein Binding
D047495:PPAR gamma; D004004:Dichlororibofuranosylbenzimidazole; D042925:Positive Transcriptional Elongation Factor B; C467972:Cdk9 protein, mouse; D042863:Cyclin-Dependent Kinase 9