HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage

摘要: Homeodomain-interacting protein kinase 2 (HIPK2) is an emerging player in cell response to genotoxic agents that senses damage intensity and contributes the cell's choice between cycle arrest apoptosis. Phosphorylation of p53 at S46, apoptosis-specific posttranslational modification, most characterized HIPK2 function lethal doses ultraviolet (UV), ionizing radiation or different anticancer drugs, such as cisplatin, roscovitine doxorubicin (DOX). Indeed, like p53, has been shown contribute effectiveness these treatments. Interestingly, p53-independent mechanisms HIPK2-induced apoptosis were described for UV tumor growth factor-β treatments; however, it unknown whether are relevant responses drugs. Because importance so-called 'p53-independent drug response' human cancer chemotherapy, we asked factor(s) might be involved HIPK2-mediated chemosensitivity. Here, show depletion by RNA interference induces resistance drugs even p53-null cells, suggesting involvement targets other than chemotherapy. In particular, found phosphorylates promotes proteasomal degradation ΔNp63α, a prosurvival ΔN isoform family member, p63. effective was require phosphorylation-induced ΔNp63α. DOX-treated interferes with ΔNp63α degradation, expression HIPK2-resistant ΔNp63α-Δ390 mutant chemoresistance. We identify T397 residue phosphorylated HIPK2, non-phosphorylatable ΔNp63α-T397A not degraded face either overexpression DOX treatment. These results indicate novel target