Open AccessSynthetic Lethality Induced by Loss of PKC and Mutated Ras
Author(s) -
Tingyao Zhu,
Lihua Chen,
Wei Du,
Takanori Tsuji,
Changyan Chen
Publication year - 2010
Publication title -
genes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.883
H-Index - 71
eISSN - 1947-6027
pISSN - 1947-6019
DOI - 10.1177/1947601909360989
Subject(s) - synthetic lethality , lethality , medicine , protein kinase c , microbiology and biotechnology , biology , genetics , signal transduction , dna repair , dna
Synthetic lethal interaction between oncogenic Ha-ras and loss of PKC has been demonstrated. Recently, the authors reported that the concurrent knockdown of PKC α and β, via upregulating PKC δ, sensitizes cells with aberrant Ras signaling to apoptosis. As a continuation of the study, using shRNA, the authors demonstrate that loss of PKC δ causes a lethal reaction in NIH3T3/Hras or prostate cancer DU145 cells that overexpress JNK. In this apoptotic process, PKC α and β are upregulated and then associated with RACK1 (an adaptor for activated PKC) and JNK. Immunoblotting analysis shows that JNK is phosphorylated, accompanied with caspase 8 cleavage. The inhibition of JNK abrogates this apoptotic process triggered by PKC δ knockdown. Interestingly, without blocking PKC δ, the concurrent overexpression of wt- or CAT-PKC α and β is insufficient to induce apoptosis in the cells. Together with the authors' previous findings, the data suggest that PKC α/β and δ function oppositely to maintain a balance that supports cells expressing v-ras to survive and prevents them from being eliminated through oncogenic stress-induced apoptosis.