Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site.
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) regulates transcription in response to prostanoid and thiazolidinedione ligands and promotes adipocyte differentiation. The amino-terminal A/B domain of this receptor contains a consensus mitogen-activated protein kinase site in a region common to PPARgamma1 and -gamma2 isoforms. The A/B domain of human PPARgamma1 was phosphorylated in vivo, and this was abolished either by mutation of serine 84 to alanine (S84A) or coexpression of a phosphoprotein phosphatase. In vitro, this domain was phosphorylated by ERK2 and JNK, and this was markedly reduced in the S84A mutant. A wild type Gal4-PPARgamma(A/B) chimera exhibited weak constitutive transcriptional activity. Remarkably, this was significantly enhanced in the S84A mutant fusion. Ligand-dependent activation by full-length mouse PPARgamma2 was also augmented by mutation of the homologous serine in the A/B domain to alanine. The nonphosphorylatable form of PPARgamma was also more adipogenic. Thus, phosphorylation of a mitogen-activated protein kinase site in the A/B region of PPARgamma inhibits both ligand-independent and ligand-dependent transactivation functions. This observation provides a potential mechanism whereby transcriptional activation by PPARgamma may be modulated by growth factor or cytokine-stimulated signal transduction pathways involved in adipogenesis.
Adams
M
M
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom.
Reginato
M J
MJ
Shao
D
D
Lazar
M A
MA
Chatterjee
V K
VK
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D017871:Calcium-Calmodulin-Dependent Protein Kinases