Regulation of MDM2 Stability After DNA Damage.
Regulation of MDM2 Stability After DNA Damage.
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DOI：
10.1002/jcp.24994
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发表时间：
2015-10
影响因子：
5.6
通讯作者：
Kurokawa M
中科院分区：
文献类型：
--
作者：
Li J;Kurokawa M
我们体内的细胞不断地暴露在各种压力和威胁之下，威胁着它们的基因组完整性。肿瘤抑制蛋白p53通过诱导凋亡细胞死亡或细胞周期阻滞，在成功防御这些威胁中起着关键作用。在非应激条件下，p53水平和活性必须保持在低水平，以防止凋亡和衰老途径的致命激活。然而，当DNA受到损伤或受到其他压力时，p53会从抑制状态中释放出来，诱导一系列细胞凋亡和细胞周期基因。相反，p53的失活可促进肿瘤不受抑制的增殖和细胞凋亡，进而导致癌变。泛素E3连接酶MDM2是p53最关键的抑制剂，它决定了细胞对各种p53激活剂的反应，包括DNA损伤。MDM2的活性受翻译后修饰控制，尤其是磷酸化。然而，越来越多的证据表明，MDM2也在蛋白质稳定性水平上受到调节，这是由泛素-蛋白酶体途径控制的。在这里，我们讨论MDM2如何在DNA损伤的反应中被调节，特别关注MDM2蛋白稳定性的调节。
Cells in our body are constantly exposed to various stresses and threats to their genomic integrity. The tumor suppressor protein p53 plays a critical role in successful defense against these threats by inducing apoptotic cell death or cell cycle arrest. In unstressed conditions, p53 levels and activity must be kept low to prevent lethal activation of apoptotic and senescence pathways. However, upon DNA damage or other stressors, p53 is released from its inhibitory state to induce an array of apoptosis and cell cycle genes. Conversely, inactivation of p53 could promote unrestrained tumor proliferation and failure to appropriately undergo apoptotic cell death, which could, in turn, lead to carcinogenesis. The ubiquitin E3 ligase MDM2 is the most critical inhibitor of p53 that determines the cellular response to various p53-activating agents, including DNA damage. MDM2 activity is controlled by post-translational modifications, especially phosphorylation. However, accumulating evidence suggests that MDM2 is also regulated at the level of protein stability, which is controlled by the ubiquitin-proteasome pathway. Here, we discuss how MDM2 can be regulated in response to DNA damage with particular focus on the regulation of MDM2 protein stability.
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