Homeodomain-interacting protein kinase 2 (HIPK2) is an emerging player in cell response to genotoxic agents that senses damage intensity and contributes to the cell's choice between cell cycle arrest and apoptosis. Phosphorylation of p53 at S46, an apoptosis-specific p53 posttranslational modification, is the most characterized HIPK2 function in response to lethal doses of ultraviolet (UV), ionizing radiation or different anticancer drugs, such as cisplatin, roscovitine and doxorubicin (DOX). Indeed, like p53, HIPK2 has been shown to contribute to the effectiveness of these treatments. Interestingly, p53-independent mechanisms of HIPK2-induced apoptosis were described for UV and tumor growth factor-beta treatments; however, it is unknown whether these mechanisms are relevant for the responses to anticancer drugs. Because of the importance of the so-called 'p53-independent apoptosis and drug response' in human cancer chemotherapy, we asked whether p53-independent factor(s) might be involved in HIPK2-mediated chemosensitivity. Here, we show that HIPK2 depletion by RNA interference induces resistance to different anticancer drugs even in p53-null cells, suggesting the involvement of HIPK2 targets other than p53 in response to chemotherapy. In particular, we found that HIPK2 phosphorylates and promotes proteasomal degradation of DeltaNp63alpha, a prosurvival DeltaN isoform of the p53 family member, p63. Indeed, effective cell response to different genotoxic agents was shown to require phosphorylation-induced proteasomal degradation of DeltaNp63alpha. In DOX-treated cells, we show that HIPK2 depletion interferes with DeltaNp63alpha degradation, and expression of a HIPK2-resistant DeltaNp63alpha-Delta390 mutant induces chemoresistance. We identify T397 as the DeltaNp63alpha residue phosphorylated by HIPK2, and show that the non-phosphorylatable DeltaNp63alpha-T397A mutant is not degraded in the face of either HIPK2 overexpression or DOX treatment. These results indicate DeltaNp63alpha as a novel target of HIPK2 in response to genotoxic drugs.
展开▼
