Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53.
Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53.
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DOI：
10.1038/onc.2010.163
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发表时间：
2010-07-15
期刊：
影响因子：
8
通讯作者：
Deng CX
中科院分区：
文献类型：
--
作者：
Fishler T;Li YY;Wang RH;Kim HS;Sengupta K;Vassilopoulos A;Lahusen T;Xu X;Lee MH;Liu Q;Elledge SJ;Ried T;Deng CX
检查点激酶1（Chk 1）是维持基因组稳定性所需的DNA损伤反应途径中的关键元件。为了研究Chk 1在乳腺肿瘤发生中的潜在作用，我们使用Cre/loxP系统破坏了它。我们发现，虽然Chk 1杂合性引起乳腺发育异常，但不足以诱导肿瘤发生。同时缺失一个拷贝的p53未能挽救发育缺陷;然而，它协同诱导Chk 1 +/−; MMTV-Cre动物的乳腺肿瘤形成，肿瘤潜伏期的中位时间约为10个月。Chk 1缺陷导致异常的优势，包括延长，多极化，错位，有丝分裂灾难和纺锤体检查点的损失，伴随着几个细胞周期调节因子，包括Mad 2的表达减少。另一方面，我们还发现Chk 1缺陷抑制了p53纯合缺失小鼠乳腺肿瘤的形成，揭示了Chk 1和p53之间的复杂关系。此外，用特异性抑制剂SB-218078抑制Chk 1或使用小发夹RNA急性缺失Chk 1可有效杀死乳腺肿瘤细胞。这些数据表明，Chk 1对于维持基因组完整性至关重要，并且是癌症的双刃剑：虽然它的抑制可以杀死癌细胞，但当细胞生长积累有利的突变时，它也会引发肿瘤发生。
Checkpoint kinase 1 (Chk1) is a key element in the DNA-damage response pathway that is required for maintaining genomic stability. To study the potential role of Chk1 in mammary tumorigenesis, we disrupted it using a Cre/loxP system. We showed that although Chk1 heterozygosity caused abnormal development of the mammary gland, it was not sufficient to induce tumorigenesis. Simultaneous deletion of one copy of p53 failed to rescue the developmental defects; however, it synergistically induced mammary tumor formation in Chk1+/−; MMTV-Cre animals with a median time to tumor latency of about 10 months. Chk1 deficiency caused a preponderance of abnormalities, including prolongation, multipolarity, misalignment, mitotic catastrophe and loss of spindle checkpoint, that are accompanied by reduced expression of several cell cycle regulators, including Mad2. On the other hand, we also showed that Chk1 deficiency inhibited mammary tumor formation in mice carrying a homozygous deletion of p53, uncovering a complex relationship between Chk1 and p53. Furthermore, inhibition of Chk1 with a specific inhibitor, SB-218078, or acute deletion of Chk1 using small hairpin RNA killed mammary tumor cells effectively. These data show that Chk1 is critical for maintaining genome integrity and serves as a double-edged sword for cancer: although its inhibition kills cancer cells, it also triggers tumorigenesis when favorable mutations are accumulated for cell growth.
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