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首页> 外文期刊>Cell cycle >A new twist in the feedback loop: stress-activated MDM2 destabilization is required for p53 activation.
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A new twist in the feedback loop: stress-activated MDM2 destabilization is required for p53 activation.

机译：反馈回路中的新变化：p53激活需要应力激活的MDM2不稳定。

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The p53 tumor suppressor is a transcription factor that is activated by diverse genotoxic and cytotoxic stresses. Upon activation, p53 prevents the proliferation of genetically unstable cells by regulating the expression of genes that initiate cell cycle arrest, apoptosis, and DNA repair. Consequently, p53 must be kept inactive in unstressed cells as its inappropriate activation can cause premature senescence and death. p53 inhibition occurs primarily through the E3 ubiquitin ligase, MDM2. Because MDM2 is also a p53 target gene, stresses paradoxically activate p53 while simultaneously increasing MDM2 expression. Therefore, a challenge has been to explain how the abundant MDM2 is prevented from inhibiting p53, thus ensuring that p53 can execute an appropriate stress response. Here we discuss a new mechanism for p53 activation involving DNA damage-induced auto-degradation of MDM2. Our data reveal that DNA damage leads to the destabilization of MDM2, which correlates with p53 stabilization and target gene induction. Conversely, p53 levels and activity decrease when MDM2 returns to a more stable state later in the stress response. The destabilization of MDM2 is required for p53 activation, as blocking MDM2 degradation via proteasome inhibition prevents p53 transactivation in DNA-damaged cells by enabling MDM2 to bind and inhibit p53. MDM2 destabilization is controlled by DNA damage-activated post-translational modifications and by its own RING domain, implying a possible role for the RING domain-interacting protein, MDMX, in regulating MDM2 stability. We propose that accelerated degradation of MDM2 limits its binding to p53 during a stress response and enables p53 to accumulate and remain active, even as p53 transcriptionally activates more MDM2. Thus, the induction of MDM2 RNA by activated p53 may create a reserve of MDM2 that can inactivate p53 once the DNA damage stimulus has abated and MDM2 is restabilized. As many tumors inactivate wild type p53 through MDM2 overexpression, exploiting the pathways that trigger MDM2 auto-degradation may be an important new strategy for chemotherapeutic intervention.
机译：p53肿瘤抑制因子是一种转录因子，可被多种遗传毒性和细胞毒性应激激活。激活后，p53通过调节启动细胞周期停滞，凋亡和DNA修复的基因的表达来防止遗传不稳定细胞的增殖。因此，p53必须在未受压的细胞中保持失活，因为其不适当的激活会导致过早衰老和死亡。 p53抑制主要通过E3泛素连接酶MDM2发生。因为MDM2也是p53的靶基因，所以压力反常激活p53，同时增加MDM2的表达。因此，挑战在于解释如何防止丰富的MDM2抑制p53，从而确保p53可以执行适当的应激反应。在这里，我们讨论了涉及DNA损伤诱导的MDM2自动降解的p53激活新机制。我们的数据表明，DNA损伤导致MDM2不稳定，这与p53稳定和靶基因诱导相关。相反，当MDM2在压力反应中稍后返回到更稳定的状态时，p53水平和活性降低。 MDM2的不稳定需要p53激活，因为通过蛋白酶体抑制来阻止MDM2降解可通过使MDM2结合并抑制p53来防止DNA损伤细胞中p53反式激活。 MDM2的去稳定作用受DNA损伤激活的翻译后修饰及其自身的RING域控制，这意味着RING域相互作用蛋白MDMX在调节MDM2稳定性中可能发挥作用。我们提出，MDM2的加速降解会限制其在应激反应期间与p53的结合，并使p53积累并保持活性，即使p53在转录上激活了更多的MDM2。因此，通过激活的p53诱导MDM2 RNA可以产生MDM2储备，一旦DNA损伤刺激消除并且MDM2重新稳定化，它可以使p53失活。由于许多肿瘤通过MDM2过表达使野生型p53失活，利用触发MDM2自降解的途径可能是化疗干预的重要新策略。

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