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1 and Negatively Regulates Its Transcriptional Activity
Department of Cell Biology (H.S.C., T.L.), Department of Molecular Biology (S.R.T.), Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, Michigan 48105; and the Department of Biological Chemistry, University of Michigan Medical School (T.L.), Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Dr. Todd Leff, Parke-Davis, Department of Cell Biology, 2800 Plymouth Road, Ann Arbor, Michigan 48105. E-mail: todd.leff{at}aa.wl.com
The peroxisome proliferator-activated receptor-
(PPAR)
transcription factor plays a pivotal role in adipocyte differentiation
and metabolic regulation. The transcriptional activity of PPAR is
positively modulated by ligand binding and negatively regulated by
phosphorylation mediated by the MEK/ERK signaling pathway. The
phosphorylation of mouse PPAR1 at Ser82 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 PPAR1. We demonstrate
that in vitro, PPAR1 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,
PPAR1 is phosphorylated at Ser82 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 MEK/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 PPAR1 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-
, would result in a reduction of PPAR transcriptional
activity and reduce the effects of PPAR ligands.
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P. M. Barger, A. C. Browning, A. N. Garner, and D. P. Kelly p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor alpha . A POTENTIAL ROLE IN THE CARDIAC METABOLIC STRESS RESPONSE J. Biol. Chem., November 21, 2001; 276(48): 44495 - 44501. [Abstract] [Full Text] [PDF]
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