Department of Experimental Oncology, Molecular Oncogenesis Laboratory, National Cancer Institute Regina Elena, Rome, Italy.
Oncogene. 2010 Aug 5;29(31):4378-87. doi: 10.1038/onc.2010.183. Epub 2010 May 31.
The p53 protein is the most studied tumor suppressor and the p53 pathway has been shown to mediate cellular stress responses that are disrupted when cancer develops. After DNA damage, p53 is activated as transcription factor to directly induce the expression of target genes involved in cell-cycle arrest, DNA repair, senescence and, importantly, apoptosis. Post-translational modifications of p53 are essential for the activation of p53 and for selection of target genes. The tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating its N-terminal serine 46 (Ser46) and facilitating Lys382 acetylation at the C-terminus. HIPK2 is activated by numerous genotoxic agents and can be deregulated in tumors by several conditions including hypoxia. Recent findings suggest that HIPK2 active/inactive protein can affect p53 function in multiple and unexpected ways. This makes p53 as well as HIPK2 interesting targets for cancer therapy. Hence, understanding the role of HIPK2 as p53 activator may provide important insights in the process of tumor progression, and may also serve as the crucial point in the diagnostic and therapeutical aspects of cancer.
p53 蛋白是研究最多的肿瘤抑制因子，已证实 p53 途径介导细胞应激反应，而当癌症发生时，这种反应会被破坏。在 DNA 损伤后，p53 作为转录因子被激活，直接诱导参与细胞周期停滞、DNA 修复、衰老的靶基因表达，重要的是，诱导细胞凋亡。p53 的翻译后修饰对于 p53 的激活和靶基因的选择至关重要。肿瘤抑制因子同源结构域相互作用蛋白激酶-2（HIPK2）通过磷酸化其 N 端丝氨酸 46（Ser46）并促进 C 端赖氨酸 382 乙酰化，是 p53 凋亡功能的关键调节因子。HIPK2 被多种遗传毒性药物激活，并且在肿瘤中可以通过多种条件（包括缺氧）失调。最近的研究结果表明，HIPK2 活性/非活性蛋白可以以多种意想不到的方式影响 p53 功能。这使得 p53 以及 HIPK2 成为癌症治疗的有趣靶点。因此，了解 HIPK2 作为 p53 激活剂的作用可能为肿瘤进展过程提供重要的见解，并可能成为癌症诊断和治疗方面的关键点。
