ATM complexes with HDM2 and promotes its rapid phosphorylation in a p53-independent manner in normal and tumor human cells exposed to ionizing radiation
ATM complexes with HDM2 and promotes its rapid phosphorylation in a p53-independent manner in normal and tumor human cells exposed to ionizing radiation
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DOI：
10.1038/sj.onc.1204020
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发表时间：
2000-12-14
期刊：
影响因子：
8
通讯作者：
Little, JB
中科院分区：
文献类型：
--
作者：
de Toledo, SM;Azzam, EI;Little, JB
为了进一步了解DNA损伤激活p53的机制，我们分析了p53和HDM 2的表达水平（鼠MDM 2的人同源物）在各种人二倍体成纤维细胞和肿瘤细胞株中在已知的p53下游效应物活化之前的时期中，在X-照射的人细胞中，HDM 2蛋白在p53中的丝氨酸/苏氨酸残基中迅速磷酸化，p14（ARF）和p73非依赖性方式。在p53野生型细胞中，HDM 2磷酸化先于p53水平的可检测的增加，并且在共济失调毛细血管扩张（AT）成纤维细胞中未观察到。用表达ATM的载体转染AT细胞恢复了在X射线照射后快速磷酸化HDM 2的能力，证实了ATM在其磷酸化中的作用。我们还表明ATM与HDM 2复合，发出HDM 2早期快速磷酸化信号的DNA损伤是X射线而不是UV型损伤的结果。在X射线照射的人类细胞中，ATM促进的HDM 2早期共价修饰可能提供了激活p53的机制。
To further understand the mechanism(s) by which DNA damage activates p53, we analysed the expression levels of p53 and HDM2 (the human homolog of murine MDM2) in various human diploid fibroblast and tumor cell strains during the period that precedes activation of known downstream effecters of p53, In X-irradiated human cells, HDM2 protein was rapidly phosphorylated in serine/threonine residues in a p53, p14(ARF) and p73-independent manner. In p53 wild-type cells, HDM2 phosphorylation precedes a detectable increase in the levels of p53 and is not observed in ataxia telangiectasia (AT) fibroblasts, The transfection of AT cells with a vector expressing ATM restored the ability to rapidly phosphorylate HDM2 following X-irradiation, confirming a role for ATM in its phosphorylation, We also show that ATM complexes with HDM2, The DNA lesions signaling the early rapid phosphorylation of HDM2 are a result of X-ray and not UV-type damage. The ATM-promoted early covalent modification of HDM2 in X-irradiated human cells may provide a mechanism to activate p53.