Induction of SOX4 by DNA damage is critical for p53 stabilization and function
Induction of SOX4 by DNA damage is critical for p53 stabilization and function
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DNA 损伤诱导 SOX4 对于 p53 稳定和功能至关重要
DOI：
10.1073/pnas.0810147106
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发表时间：
2009-03-10
影响因子：
11.1
通讯作者：
Zhang, Xue-Min
中科院分区：
文献类型：
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作者：
Pan, Xin;Zhao, Jie;Zhang, Xue-Min
DNA损伤反应(DDR)起着肿瘤发生屏障的作用，DDR机制中的任何缺陷都可能导致癌症。SOX4在许多类型的肿瘤中表达升高；然而，它在DDR中的作用仍然很大程度上是未知的。在这里，我们证明了一种新的DNA损伤传感器Sox4是激活P53肿瘤抑制因子以响应DNA损伤所必需的。值得注意的是，Sox4通过阻断MDM2介导的P53泛素化和降解来与P53蛋白相互作用并使其稳定。此外，Sox4通过与p300/CBP相互作用，促进p300/CBP/P53复合体的形成，从而促进P53乙酰化。与这些结果一致，Sox4促进细胞周期停滞和凋亡，并以P53依赖的方式抑制肿瘤形成。因此，这些发现突出了Sox4是调控DDR相关癌症的潜在关键因素。
DNA damage response (DDR) acts as a tumorigenesis barrier, and any defects in the DDR machinery may lead to cancer. SOX4 expression is elevated in many types of tumors; however, its role in DDR is still largely unknown. Here, we show that SOX4, a new DNA damage sensor, is required for the activation of p53 tumor suppressor in response to DNA damage. Notably, SOX4 interacts with and stabilizes p53 protein by blocking Mdm2-mediated p53 ubiquitination and degradation. Furthermore, SOX4 enhances p53 acetylation by interacting with p300/CBP and facilitating p300/CBP/p53 complex formation. In concert with these results, SOX4 promotes cell cycle arrest and apoptosis, and it inhibits tumorigenesis in a p53-dependent manner. Therefore, these findings highlight SOX4 as a potential key factor in regulating DDR-associated cancer.