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J. Biol. Chem., Vol. 280, Issue 11, 10109-10118, March 18, 2005

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Peroxisome Proliferator-activated Receptor -independent Activation of p38 MAPK by Thiazolidinediones Involves Calcium/Calmodulin-dependent Protein Kinase II and Protein Kinase R

CORRELATION WITH ENDOPLASMIC RETICULUM STRESS^*

Olivia S. Gardner, Chung-Wai Shiau¶, Ching-Shih Chen¶, and Lee M. Graves||**

From the Curriculum in Toxicology, the ^||Department of Pharmacology, University of North Carolina at Chapel Hill, North Carolina 27599 and the ^¶Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210

The thiazolidinediones (TZDs) are synthetic peroxisome proliferator-activated receptor (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 PKR (double-stranded RNA-activated protein kinase)-like endoplasmic reticulum kinase/pancreatic eIF2 kinase, and that 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. Although 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.

Received for publication, September 10, 2004 , and in revised form, January 12, 2005.

^* This work was supported in part by the National Institute of Health with Public Health Service Grants and the Environmental Protection Agency Science to Achieve Results Award R-82921401-0. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Susan G. Komen Breast Cancer Foundation.

^** To whom correspondence should be addressed: Dept. of Pharmacology, University of North Carolina at Chapel Hill, CB# 7365, Chapel Hill, NC 27599-7365. Tel.: 919-966-0915; Fax: 919-966-5640; E-mail: lmg{at}med.unc.edu.

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