Roles of PKC isoforms in the induction of apoptosis elicited by aberrant Ras

Abstract

Emerging evidence indicates that suppression of protein kinase C (PKC) renders the susceptibility of cells expressing mutated ras to apoptosis. Although the effort has been made, the underlying molecular mechanisms are not fully understood. In this study, using small hairpin RNAs (shRNAs) or PKC inhibitor, we show that the concurrent suppression of PKC-α and Β induces cells ectopically expressing v-ras to undergo apoptosis. In this apoptotic process, PKC-is upregulated and translocated from the cytosol to the nucleus. The activated PKC-associates with and phosphorylates p73 to initiate apoptosis. In this apoptotic process, Akt seems to be downstream of oncogenic Ras. Moreover, overexpression of PKC-, without co-suppression of PKC-α and Β, is not apoptotic to the cells, suggesting that PKC-and PKC-α/Β function oppositely to facilitate cells harboring v-ras to survive. Thus, our study shows that PKC-α and Β are necessary for sustaining the homeostasis in cells containing a hyperactive Ras. The abrogation of these two isoforms switches on the p73-regulated apoptotic machinery through the activation of PKC-. © 2010 Macmillan Publishers Limited All rights reserved.