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J. Biol. Chem., Vol. 280, Issue 25, 23643-23652, June 24, 2005

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Roles of Tyrosine Phosphorylation and Cleavage of Protein Kinase C in Its Protective Effect Against Tumor Necrosis Factor-related Apoptosis Inducing Ligand-induced Apoptosis^*

Hana Okhrimenko, Wei Lu, Cunli Xiang, Donghong Ju, Peter M. Blumberg¶, Ruth Gomel, Gila Kazimirsky, and Chaya Brodie||

From the Gonda (Goldschmied) Medical Diagnosis Research Center, Faculty of Life-Sciences, Bar-Ilan University, Ramat-Gan, Israel 52900, the Department of Neurosurgery, Hermelin Brain Tumor Center, Henry Ford Hospital, Detroit, Michigan 48202, and the ^¶Laboratory of Cellular Carcinogenesis and Tumor Promotion, NCI, National Institutes of Health, Bethesda, Maryland 20892

Protein kinase C (PKC) regulates cell apoptosis in a cell- and stimulus-specific manner. Here, we studied the role of PKC in the apoptotic effect of TRAIL in glioma cells. We found that transfection of the cells with a PKC kinase-dead mutant (K376R) or with a small interfering RNA targeting the PKC mRNA increased the apoptotic effect of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), whereas overexpression of PKC decreased it. PKC acted downstream of caspase 8 and upstream of cytochrome c release from the mitochondria. TRAIL induced cleavage of PKC within 2–3 h of treatment, which was abolished by caspase 3, 8, and 9 inhibitors. The cleavage of PKC was essential for its protective effect because overexpression of a caspase-resistant mutant (PKCD327A) did not protect glioma cells from TRAIL-induced apoptosis but rather increased it. TRAIL induced translocation of PKC to the perinuclear region and the endoplasmic reticulum and phosphorylation of PKC on tyrosine 155. Using a PKCY155F mutant, we found that the phosphorylation of PKC on tyrosine 155 was essential for the cleavage of PKC in response to TRAIL and for its translocation to the endoplasmic reticulum. In addition, phosphorylation of PKC on tyrosine 155 was necessary for the activation of AKT in response to TRAIL. Our results indicate that PKC protects glioma cells from the apoptosis induced by TRAIL and implicate the phosphorylation of PKC on tyrosine 155 and its cleavage as essential factors in the anti-apoptotic effect of PKC.

Received for publication, February 7, 2005 , and in revised form, March 15, 2005.

^* This work was supported by a grant from the James S. McDonnell Foundation 21st Century Scientist Award/Brain Cancer Research (to C. B.). 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.

^|| To whom correspondence should be addressed: Hermelin Brain Tumor Center, Dept. of Neurosurgery, Henry Ford Hospital, Detroit, MI 48202. E-mail: chaya{at}mail.biu.ac.il.

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