REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA ACTIVITY BY MITOGEN-ACTIVATED PROTEIN-KINASE

Adipocyte differentiation is regulated both positively and negatively by external growth factors such as insulin, platelet-derived growth fa ctor (PDGF), and epidermal growth factor (EGF). A key component of the adipocyte differentiation process is PPAR gamma, peroxisomal prolifer ator-activated receptor gamma. To determine the relationship between P PAR gamma activation and growth factor stimulation in adipogenesis, we investigated the effects of PDGF and EGF on PPAR gamma 1 activity. PD GF treatment decreased ligand-activated PPAR gamma 1 transcriptional a ctivity in a transient reporter assay. In vivo [P-32]orthophosphate la beling experiments demonstrated that PPAR gamma 1 is a phosphoprotein that undergoes EGF-stimulated MEK/mitogen-activated protein (MAP) kina se-dependent phosphorylation. Purified PPAR gamma 1 protein was phosph orylated in vitro by recombinant activated MAP kinase. Examination of the PPAR gamma 1 sequence revealed a single MAP kinase consensus recog nition site at Ser(82). Mutation of Ser(82) to Ala inhibited both in v itro and in vivo phosphorylation and growth factor-mediated transcript ional repression. Therefore, phosphorylation of PPAR gamma 1 by MAP ki nase contributes to the reduction of PPAR gamma 1 transcriptional acti vity by growth factor treatment.