ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation
ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation
复制标题
DOI：
10.4161/cc.4.9.1981
复制
发表时间：
2005-09-01
期刊：
影响因子：
4.3
通讯作者：
Jochemsen, AG
中科院分区：
文献类型：
--
作者：
Meulmeester, E;Pereg, Y;Jochemsen, AG
p53肿瘤抑制蛋白在保护基因组完整性方面具有重要作用。在正常情况下，Mdmx和Mdm2控制p53的活性。这两种蛋白质都抑制p53的转录调节，而Mdm2也作为E3泛素连接酶发挥作用，靶向p53和Mdmx进行蛋白酶体降解。HAUSP通过p53的直接去泛素化来抵消Mdm 2的去稳定作用。随后，HAUSP被证明去泛素化Mdm2和Mdmx，从而稳定这些蛋白质。ATM蛋白激酶是p53通路响应DNA中的双链断裂（DSB）的关键调节剂。ATM通过直接磷酸化p53，调节p53蛋白的额外翻译后修饰，以及影响两种p53调节因子：Mdm 2和Mdmx，来微调p53对DNA损伤的反应。ATM直接或间接诱导Mdm 2和Mdmx磷酸化，导致这些蛋白的活性和稳定性降低。我们最近通过显示ATM依赖性磷酸化降低了它们对去泛素化酶HAUSP的亲和力，提供了Mdm 2和Mdmx稳定性降低的机制。总之，新出现的图片描绘了一个精心制作的，但微调，ATM介导的控制p53激活和稳定后DNA损伤。进一步深入了解ATM转换HAUSP，Mdmx，Mdm2和p53之间的相互作用以促进p53激活的机制可能为癌症治疗的p53途径的治疗干预提供新的工具。
The p53 tumor suppressor protein has a major role in protecting genome integrity. Under normal circumstances Mdmx and Mdm2 control the activity of p53. Both proteins inhibit the transcriptional regulation by p53, while Mdm2 also functions as an E3 ubiquitin ligase to target both p53 and Mdmx for proteasomal degradation. HAUSP counteracts the destabilizing effect of Mdm2 by direct deubiquitination of p53. Subsequently, HAUSP was shown to deubiquitinate Mdm2 and Mdmx, thereby stabilizing these proteins. The ATM protein kinase is a key regulator of the p53 pathway in response to double strand breaks ( DSBs) in the DNA. ATM fine-tunes p53' s response to DNA damage by directly phosphorylating it, by regulating additional post-translational modifications of this protein, and by affecting two p53 regulators: Mdm2 and Mdmx. ATM directly and indirectly induces Mdm2 and Mdmx phosphorylation, resulting in decreased activity and stability of these proteins.We recently provided a mechanism for the reduced stability of Mdm2 and Mdmx by showing that ATM-dependent phosphorylation lowers their affinity for the deubiquitinating enzyme HAUSP. Altogether, the emerging picture portrays an elaborate, but fine-tuned, ATM-mediated control of p53 activation and stabilization following DNA damage. Further insight into the mechanism by which ATM switches the interactions between HAUSP, Mdmx, Mdm2 and p53, to favor p53 activation may offer new tools for therapeutic intervention in the p53 pathway for cancer treatment.