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-alpha and beta induces cells ectopically expressing v-ras to undergo apoptosis. In this apoptotic process, PKC-delta is upregulated and translocated from the cytosol to the nucleus. The activated PKC-delta associates with and phosphorylates p73 to initiate apoptosis. In this apoptotic process, Akt seems to be downstream of oncogenic Ras. Moreover, overexpression of PKC-delta, without co-suppression of PKC-alpha and beta, is not apoptotic to the cells, suggesting that PKC-delta and PKC-alpha/beta function oppositely to facilitate cells harboring v-ras to survive. Thus, our study shows that PKC-alpha and beta 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-delta.