Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo
Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo
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DOI：
10.1038/emboj.2010.218
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发表时间：
2010-10-20
期刊：
影响因子：
11.4
通讯作者：
Nakanishi, Makoto
中科院分区：
文献类型：
--
作者：
Niida, Hiroyuki;Murata, Kazuhiro;Nakanishi, Makoto
尽管Chk1和Chk2与重要的癌症信号相关联，表明这些激酶具有肿瘤抑制因子的功能，但Chk1(+/-)和Chk2(-/-)小鼠在不受干扰的条件下都不容易患癌症。我们在这里展示了Chk1(+/-)Chk2(-/-)和Chk1(+/-)Chk2(+/-)小鼠具有进行性易患癌症的表型。单个Chk1等位基因的缺失损害了G2/M检查点的功能，该功能不受Chk2缺失的进一步影响，而Chk1和Chk2协同影响G1/S和S内的检查点。根据DNA损伤的类型，DNA修复需要两种或其中一种激酶。在未受干扰的条件下，双突变小鼠的胚胎成纤维细胞显示出较高水平的P53，并伴有自发的DNA损伤，但在S23处未能磷酸化P53，并在额外的DNA损伤时进一步诱导P53的表达。Chk1和Chk2显然都不是p53或Rb依赖的癌基因诱导的衰老所必需的。我们的结果表明，双Chk突变导致高水平的自发DNA损伤，但无法消除DNA损伤的细胞，这最终可能增加癌症的易感性，而不是衰老。EMBO期刊(2010)29,3558-3570。DOI：10.1038/Inempj.2010.218；2010年9月10日在线发布主题类别：基因组稳定性与动力学；疾病分子生物学
Although the linkage of Chk1 and Chk2 to important cancer signalling suggests that these kinases have functions as tumour suppressors, neither Chk1(+/-) nor Chk2(-/-) mice show a predisposition to cancer under unperturbed conditions. We show here that Chk1(+/-) Chk2(-/-) and Chk1(+/-) Chk2(+/-) mice have a progressive cancer-prone phenotype. Deletion of a single Chk1 allele compromises G2/M checkpoint function that is not further affected by Chk2 depletion, whereas Chk1 and Chk2 cooperatively affect G1/S and intra-S phase checkpoints. Either or both of the kinases are required for DNA repair depending on the type of DNA damage. Mouse embryonic fibroblasts from the double-mutant mice showed a higher level of p53 with spontaneous DNA damage under unperturbed conditions, but failed to phosphorylate p53 at S23 and further induce p53 expression upon additional DNA damage. Neither Chk1 nor Chk2 is apparently essential for p53- or Rb-dependent oncogene-induced senescence. Our results suggest that the double Chk mutation leads to a high level of spontaneous DNA damage, but fails to eliminate cells with damaged DNA, which may ultimately increase cancer susceptibility independently of senescence. The EMBO Journal (2010) 29, 3558-3570. doi:10.1038/emboj.2010.218; Published online 10 September 2010Subject Categories: genome stability & dyanamics; molecular biology of disease