A common gain of function of p53 cancer mutants in inducing genetic instability.
A common gain of function of p53 cancer mutants in inducing genetic instability.
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DOI：
10.1038/onc.2009.376
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发表时间：
2010-02-18
期刊：
影响因子：
8
通讯作者：
Xu, Y.
中科院分区：
文献类型：
--
作者：
Liu, D. P.;Song, H.;Xu, Y.
关键的肿瘤抑制基因p53在超过一半的人类癌症中发生突变。P53癌基因突变大多为错义突变，可分为直接破坏P53的DNA结合基序的接触性突变和对P53构象影响不大的结构突变。许多p53癌突变，包括热点突变(R175H、R248W和R273H)，不仅失去了P53依赖的抑癌活性，而且还获得了新的促癌活性。因此，阐明p53癌突变体的致癌功能是至关重要的。利用人源化的p53突变敲入小鼠模型，我们已经鉴定出最常见的p53接触突变(R273H和R248W)和结构突变(R175H)具有共同的致癌功能。这种功能的获得使依赖于Mre11/ATM的DNA损伤反应失活，导致染色体易位和G2/M检查点缺陷。考虑到ATM在维持对许多癌症治疗的遗传反应和治疗反应中的关键作用，鉴定这种常见的p53癌突变体的功能获得将对很大一部分同时表达接触性和结构性突变体的人类癌症的耐药性具有重要意义。
The critical tumor suppressor p53 is mutated in over half of all human cancers. The majority of p53 cancer mutations are missense mutations, which can be classified into contact mutations that directly disrupt the DNA-binding motif of p53 but have modest impact on p53 conformation and structural mutations that greatly disrupt p53 conformation. Many p53 cancer mutants, including the hotspot mutations (R175H, R248W and R273H), not only lose p53-dependent tumor suppressor activities, but also acquire new oncogenic activities to promote cancer. Therefore, it is critical to elucidate the gain of oncogenic function of p53 cancer mutants. Employing humanized p53 mutant knock-in mouse models, we have identified a gain of oncogenic function shared by the most common p53 contact mutants (R273H and R248W) and structural mutant (R175H). This gain of function inactivates Mre11/ATM-dependent DNA damage responses, leading to chromosomal translocation and defective G2/M checkpoint. Considering the critical roles of ATM in maintaining genetic responses and therapeutic responses to many cancer treatments, the identification of this common gain of function of p53 cancer mutants will have important implication on the drug resistance of a significant portion of human cancers that express both the contact and structural p53 cancer mutants.
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