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Papers In Press, published online ahead of print January 13, 2005
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365
Corresponding Author: lmg{at}med.unc.edu
The thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor
J. Biol. Chem, 10.1074/jbc.M410445200
Submitted on September 10, 2004
Revised on January 12, 2005
Accepted on January 13, 2005
PPARgamma-independent activation of p38 MAPK by thiazolidinediones involves calcium/calmodulin-dependent protein kinase II and protein kinase R: Correlation with endoplasmic reticulum stress
(PPAR) ligands that promote increased insulin sensitivity in type II diabetic patients. In addition to their ability to improve glucose homeostasis, TZDs also exert anti-proliferative effects by a mechanism that is unclear. Our laboratory has shown that two TZDs, ciglitazone and troglitazone, rapidly induce calcium-dependent p38 mitogen-activated protein kinase (MAPK) phosphorylation in liver epithelial cells. Here, we further characterize the mechanism responsible for p38 MAPK activation by PPAR ligands and correlate this with the induction of endoplasmic reticulum (ER) stress. Specifically, we show that TZDs rapidly activate the ER stress-responsive pancreatic eukaryotic initiation factor 2
(eIF2) kinase or PERK as well as double-stranded RNA-activated protein kinase (PKR); activation of these kinases is correlated with subsequent eIF2 phosphorylation. Interestingly, PPAR ligands not only activated calcium/calmodulin-dependent kinase II (CaMKII) 2-fold over control, but the selective CaMKII inhibitor, KN-93, attenuated MKK3/6 and p38 as well as PKR and eIF2 phosphorylation. While CaMKII was not affected by inhibition of PKR with 2-aminopurine, phosphorylation of MKK3/6 and p38 as well as eIF2 were significantly reduced. Collectively, these data provide evidence that CaMKII is a regulator of PKR-dependent p38 and eIF2 phosphorylation in response to ER calcium depletion by TZDs. Furthermore, using structural derivatives of TZDs that lack PPAR ligand-binding activity as well as a PPAR antagonist, we show that activation of these kinase signaling pathways is PPAR independent.
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