HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage
HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage
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DOI：
10.1038/onc.2011.182
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发表时间：
2011-12-01
期刊：
影响因子：
8
通讯作者：
Soddu, S.
中科院分区：
文献类型：
--
作者：
Lazzari, C.;Prodosmo, A.;Soddu, S.
同源结构域相互作用蛋白激酶2（HIPK 2）是一个新兴的球员在细胞反应的遗传毒性剂，感觉损伤强度，并有助于细胞之间的选择细胞周期阻滞和凋亡。p53在S46处的磷酸化（一种凋亡特异性p53翻译后修饰）是响应于致死剂量的紫外线（UV）、电离辐射或不同抗癌药物（如顺铂、roscovitine和阿霉素（DOX））的最特征性HIPK 2功能。事实上，与p53一样，HIPK 2已被证明有助于这些治疗的有效性。有趣的是，HIPK 2诱导的细胞凋亡的p53非依赖性机制被描述为UV和肿瘤生长因子-β治疗;然而，尚不清楚这些机制是否与抗癌药物的反应相关。由于所谓的“p53非依赖性细胞凋亡和药物反应”在人类癌症化疗中的重要性，我们询问p53非依赖性因子是否可能参与HIPK 2介导的化疗敏感性。在这里，我们表明，HIPK 2耗尽RNA干扰诱导耐药不同的抗癌药物，即使在p53-null细胞，表明参与HIPK 2靶点以外的p53在响应化疗。特别是，我们发现HIPK 2磷酸化并促进Delta Np 63 α的蛋白酶体降解，Delta Np 63 α是p53家族成员p63的促生存Delta N同种型。事实上，对不同遗传毒性剂的有效细胞应答显示需要Delta Np 63 α的磷酸化诱导的蛋白酶体降解。在DOX处理的细胞中，我们发现HIPK 2耗尽干扰Delta Np 63 α降解，并且HIPK 2抗性Delta Np 63 α-Delta 390突变体的表达诱导化学抗性。我们将T397鉴定为被HIPK 2磷酸化的Delta Np 63 α残基，并表明不可磷酸化的Delta Np 63 α-T397 A突变体在HIPK 2过表达或DOX处理的情况下不降解。这些结果表明Delta Np 63 α是响应遗传毒性药物的HIPK 2的新靶点。Oncogene（2011）30，4802-4813; doi：10.1038/onc.2011.182; 2011年5月23日在线发表
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 Delta Np63 alpha, a prosurvival Delta N isoform of the p53 family member, p63. Indeed, effective cell response to different genotoxic agents was shown to require phosphorylation-induced proteasomal degradation of Delta Np63 alpha. In DOX-treated cells, we show that HIPK2 depletion interferes with Delta Np63 alpha degradation, and expression of a HIPK2-resistant Delta Np63 alpha-Delta 390 mutant induces chemoresistance. We identify T397 as the Delta Np63 alpha residue phosphorylated by HIPK2, and show that the non-phosphorylatable Delta Np63 alpha-T397A mutant is not degraded in the face of either HIPK2 overexpression or DOX treatment. These results indicate Delta Np63 alpha as a novel target of HIPK2 in response to genotoxic drugs. Oncogene (2011) 30, 4802-4813; doi: 10.1038/onc.2011.182; published online 23 May 2011