Inhibition of Thr-55 phosphorylation restores p53 nuclear localization and sensitizes cancer cells to DNA damage
Inhibition of Thr-55 phosphorylation restores p53 nuclear localization and sensitizes cancer cells to DNA damage
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DOI：
10.1073/pnas.0804608105
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发表时间：
2008-11-04
影响因子：
11.1
通讯作者：
Liu, Xuan
中科院分区：
文献类型：
--
作者：
Cai, Xin;Liu, Xuan
p53 肿瘤抑制因子会响应 DNA 损伤而诱导细胞生长停滞和细胞凋亡。由于这些功能主要是通过 p53 的转录特性实现的，因此该蛋白的核定位至关重要。事实上，野生型 p53 细胞质定位异常的肿瘤通常表现出对 DNA 损伤的反应受损。在本研究中，我们报告 Thr-55 磷酸化诱导 p53 与核输出因子 CRM1 结合，从而导致 p53 核输出。我们进一步表明，MDM2 还促进 CRM1-p53 关联，并且该过程需要 Thr-55 磷酸化。有趣的是，通过膳食黄酮类芹菜素抑制 Thr-55 磷酸化，可以特异性阻断 CRM1-p53 关联，恢复 p53 核定位，并使细胞质定位野生型 p53 的肿瘤细胞对 DNA 损伤敏感。这些数据提供了通过翻译后修饰调节 p53 核定位的见解，并为针对野生型 p53 细胞质定位异常引起的癌症提供了一种靶向治疗途径。
The p53 tumor suppressor induces cell growth arrest and apoptosis in response to DNA damage. Because these functions are achieved largely by the transcriptional properties of p53, nuclear localization of the protein is essential. Indeed, the tumors with aberrant cytoplasmic localization of wild-type p53 often exhibit an impaired response to DNA damage. In this study, we report that Thr-55 phosphorylation induces the association of p53 with the nuclear export factor CRM1, leading to p53 nuclear export. We further show that MDM2 also promotes the CRM1-p53 association and Thr-55 phosphorylation is required for this process. Interestingly, inhibition of Thr-55 phosphorylation by a dietary flavonoid, apigenin, specifically blocks the CRM1-p53 association, restores p53 nuclear localization, and sensitizes tumor cells with cytoplasm localized wild-type p53 to DNA damage. These data provide insights into the regulation of p53 nuclear localization by post-translational modification and suggest an avenue for targeted therapy for cancers caused by aberrant cytoplasm localization of wild-type p53.