c-Jun N-terminal kinase phosphorylates peroxisome proliferator-activated receptor-γ1 and negatively regulates its transcriptional activity

The peroxisome proliferator-activated receptor-gamma (PPAR gamma) transcription factor plays a pivotal role in adipocyte differentiation and metabolic regulation. The transcriptional activity of PPAR gamma is positively modulated by ligand binding and negatively regulated by phosphorylation mediated by the MEK/ERK signaling pathway. The phosphorylation of mouse PPAR gamma 1 at Ser(82) by ERK causes a decrease in both basal and ligand-dependent transcriptional activity. In this report we examined the ability of other mitogen-activated protein kinase family members to phosphorylate PPAR gamma 1. We demonstrate that in vitro. PPAR gamma 1 is efficiently phosphorylated by JNK/SAPK (c-Jun N-terminal kinase or stress-activated protein kinase) but only weakly phosphorylated by p38. In transfected 293T cells, PPAR gamma 1 is phosphorylated at Ser(82) in response to known JNK activators such as UV irradiation and anisomycin treatment. This phosphorylation is not blocked by either the specific MEK inhibitor PD98059 or the p38 inhibitor SB203580, indicating that it is independent of the MEW ERK and p38 signaling pathways. Finally, in transient transfection reporter assays, activation of JNK by anisomycin or by overexpression of MKK4 (the upstream JNK kinase) decreased ligand-dependent PPAR gamma 1 transcriptional activity. These results suggest that the activation of the JNK/SAPK pathway by extracellular signals, perhaps by inflammatory cytokines such as tumor necrosis factor-alpha, would result in a reduction of PPAR gamma transcriptional activity and reduce the effects of PPAR gamma ligands.