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Cell Growth & Differentiation Vol. 13, 237-246, May 2002
© 2002 American Association for Cancer Research

Protein Kinase C{delta} Overexpression Enhances Radiation Sensitivity via Extracellular Regulated Protein Kinase 1/2 Activation, Abolishing the Radiation-induced G2-M Arrest1

Yoon-Jin Lee, Jae-Won Soh, Nicholas M. Dean, Chul-Koo Cho, Tae-Hwan Kim, Su-Jae Lee2 and Yun-Sil Lee2,,3

Laboratory of Radiation Effect, Korea Cancer Center Hospital, Seoul 139-706, Korea [Y-J. L., C-K. C., T-H. K, S-J. L., Y-S. L.]; Division of Molecular Life Sciences, Ewha Womans University, Seoul 120-750, Korea [Y-J. L.]; Department of Molecular Pharmacology, ISIS Pharmaceuticals, Carlsbad, California 92008 [N. M. D]; and Department of Biochemistry and Molecular Biophysics and Herbert Comprehensive Cancer Center, Columbia University, New York, New York 10032 [J-W. S]

Protein kinase C (PKC) has been widely implicated in regulation ofcell growth/cell cycle progression and apoptosis. However,the role of PKC{delta} in radiosensitivity and cell cycle regulation remains unclear. Overexpression of PKC{delta} increased Ca2+-independent PKC activity without altering other PKC isoforms (PKC{alpha}, -ß1, -{epsilon}, and -{zeta}), and extracellular regulated protein kinase (ERK) 1/2 activity was also increased in PKC{delta}-specific manner. A clonogenic survival assay showed that PKC{delta}-overexpressed cells had more radiosensitivity and pronounced induction of apoptosis than control cells. Flow cytometric analysis revealed that PKC{delta} made the cells escape from radiation-induced G2-M arrest. Moreover, p53 and p21Waf induction by radiation were higher in PKC{delta}-overexpressed cells than control cells, and PKC{delta}-mediated apoptosis was reduced, when radiation-induced ERK1/2 activity was inhibited by PD98059. Furthermore, PKC{delta} antisense and rottlerin, PKC inhibitor-abrogated PKC{delta}-mediated radiosensitivity and reduced ERK1/2 activity to the control vector level. These results demonstrated that PKC{delta} overexpression enhanced radiation-induced apoptosis and radiosensitivity via ERK1/2 activation, thereby abolishing the radiation-induced G2-M arrest and finally apoptosis.




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Copyright © 2002 by the American Association of Cancer Research.