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 (PPAR gamma) 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 PPAR gamma 1 and -gamma 2 isoforms. The A/B domain of human PPAR gamma 1 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-PPAR gamma(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 PPAR gamma 2 was also augmented by mutation of the homologous serine in the A/B domain to alanine. The nonphosphorylatable form of PPAR gamma was also more adipogenic. Thus, phosphorylation of a mitogen-activated protein kinase site in the A/B region of PPAR gamma inhibits both ligand-independent and ligand-dependent transactivation functions. This observation provides a potential mechanism whereby transcriptional activation by PPAR gamma may be modulated by growth factor or cytokine-stimulated signal transduction pathways involved in adipogenesis.