Collaboration of Brca1 and Chk2 in tumorigenesis
Collaboration of Brca1 and Chk2 in tumorigenesis
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DOI：
10.1101/gad.1192704
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发表时间：
2004-05-15
影响因子：
10.5
通讯作者：
Hakem, R
中科院分区：
文献类型：
--
作者：
McPherson, JP;Lemmers, N;Hakem, R
Brca 1的破坏导致细胞死亡或肿瘤发生，这取决于细胞环境。p53的失活有助于Brca 1相关的肿瘤易感性。然而，在缺乏Brca 1的情况下，p53依赖性检查点/凋亡信号的激活知之甚少。在这里，我们表明，Chk 2失活是部分相当于p53失活，在Chk 2缺陷促进发展，生存和增殖的Brca 1缺陷的T细胞的基因组完整性为代价。发现Brca 1缺乏导致Chk 2磷酸化和Chk 2依赖性积累和p53激活。此外，Chk 2和Brca 1的失活在乳腺癌中是协同的。我们的研究结果确定了Chk 2作为Brca 1缺乏症激活的DNA损伤信号通路的一个组成部分的关键作用。
Disruption of Brca1 results in cellular demise or tumorigenesis depending on cellular context. Inactivation of p53 contributes to Brca1-associated tumor susceptibility. However the activation of p53-dependent checkpoint/apoptotic signaling in the absence of Brca1 is poorly understood. Here, we show that Chk2 inactivation is partially equivalent to p53 inactivation, in that Chk2 deficiency facilitates the development, survival, and proliferation of Brca1-deficient T cells at the expense of genomic integrity. Brca1 deficiency was found to result in Chk2 phosphorylation and the Chk2-dependent accumulation and activation of p53. Furthermore, inactivation of Chk2 and Brca1 was cooperative in breast cancer. Our findings identify a critical role for Chk2 as a component of the DNA damage-signaling pathway activated in response to Brca1 deficiency.