Phospho-?Np63?/Rpn13-dependent regulation of LKB1 degradation modulates autophagy in cancer cells.

ABSTRACT: Oxidative stress was shown to promote the translocation of Ataxia-telangiectasia mutated (ATM) to cytoplasm and trigger the LKB1-AMPK-tuberin pathway leading to a down-regulation of mTOR and subsequently inducing the programmed cell death II (autophagy). Cisplatin was previously found to induce the ATM-dependent phosphorylation of ?Np63? in squamous cell carcinoma (SCC) cells. In this study, phosphorylated (p)-?Np63? was shown to bind the ATM promoter, to increase the ATM promoter activity and to enhance the ATM cytoplasmic accumulation. P-?Np63? protein was further shown to interact with the Rpn13 protein leading to a proteasome-dependent degradation of p-?Np63? and thereby protecting LKB1 from the degradation. In SCC cells (with an altered ability to support the ATM-dependent ?Np63? phosphorylation), the non-phosphorylated ?Np63? protein failed to form protein complexes with the Rpn13 protein and thereby allowing the latter to bind and target LKB1 into a proteasome-dependent degradation pathway thereby modulating a cisplatin-induced autophagy. We thus suggest that SCC cells sensitive to cisplatin-induced cell death are likely to display a greater ratio of p-?Np63?/non-phosphorylated ?Np63? than cells with the innate resistant/impaired response to a cisplatin-induced cell death. Our data also suggest that the choice made by Rpn13 between p-?Np63? or LKB1 to be targeted for degradation is critical for cell death decision made by cancer cells in response to chemotherapy.

SUBMITTER: Huang Y 

PROVIDER: S-EPMC3034184 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other