PKC alpha-activation is a key signaling event governing cell growth, stress-resistance, and drug-resistance. Our recent studies demonstrated that DOX-resistance mediating effects of PKC alpha require the presence of RLIP76, and their concerted action is sufficient to explain intrinsic DOX-resistance of NSCLC [S.S. Singhal, D. Wickramarachchi, J. Singhal, S. Yadav, Y.C. Awasthi, et al., Determinants of differential doxorubicin sensitivity between SCLC and NSCLC. FEBS Lett. 580 (2006) 2258-2264]. Present studies were carried out to further explore the suggestion from the previous studies that the mitogenic effects of PKC alpha also require RLIP76. RLIP76(-/-) MEFs were resistant to PKC alpha-depletion mediated growth inhibition, as well as to the PKC alpha-dependent mitogen, phorbol 12-myristate 13-acetate (PMA). Augmenting cellular levels of RLIP76 using purified recombinant RLIP76 increased growth rate in all cells, and restored the sensitivity of RLIP76(-/-) MEFs to both inhibition through PKC alpha-depletion and stimulation through PMA. These results show that RLIP76 is a necessary down-stream effector for PKC alpha-mediated mitogenesis. (c) 2006 Elsevier Inc. All rights reserved.