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首页> 外文期刊>Cell cycle >Unlike p53, p27 failed to exhibit an anti-tumor genetic interaction with Ku80.
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Unlike p53, p27 failed to exhibit an anti-tumor genetic interaction with Ku80.

机译：与p53不同，p27无法与Ku80表现出抗肿瘤遗传相互作用。

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Ku80 is often referred to as a tumor suppressor since it maintains the genome by repairing DNA double-strand breaks (DSBs) via the nonhomologous end joining (NHEJ) pathway. Even though Ku80 deletion causes hypersensitivity to gamma-radiation, DNA damage and chromosomal rearrangements, Ku80-mutant mice exhibit very low cancer levels. We previously hypothesized these low cancer levels were caused by enhanced cell cycle checkpoints that responded to inefficiently repaired DNA damage because Ku80-mutant fibroblasts exhibit premature cellular senescence that was dependent on a p53-mediated DNA damage response. In addition, Ku80 and p53 show a genetic interaction to suppress pro-B cell lymphoma and medulloblastoma. Here we tested for a similar anti-tumor genetic interaction between Ku80 and the cyclin kinase inhibitor, p27(Kip1) (p27) since p27 mutant mice showed elevated levels of pituitary adenoma that were exacerbated by gamma-radiation-induced DNA damage (damage repaired by Ku80). We found that deleting both Ku80 and p27 did not exacerbate cancer as compared to either single mutant. In addition, fibroblasts deleted for both exhibited premature cellular senescence similar to Ku80-mutant fibroblasts. Thus, p27 did not exhibit an obvious genetic interaction with Ku80 to suppress tumors. This observation suggests that DNA damage (or DNA damage responses) induced by either gamma-radiation or Ku80 deletion are not equivalent since gamma-radiation exacerbates oncogenesis in mice deleted for either p53 or p27 while Ku80 deletion exacerbates oncogenesis for only the former genotype.
机译：Ku80通常被称为肿瘤抑制因子，因为它通过非同源末端连接（NHEJ）途径修复DNA双链断裂（DSB）来维持基因组。尽管Ku80缺失会导致对γ射线辐射超敏反应，DNA损伤和染色体重排，但Ku80突变小鼠表现出非常低的癌症水平。我们以前假设这些低癌症水平是由细胞周期检查点增强引起的，该检查点对无效修复的DNA损伤有反应，因为Ku80突变的成纤维细胞表现出过早的细胞衰老，这取决于p53介导的DNA损伤反应。另外，Ku80和p53显示出抑制pro-B细胞淋巴瘤和髓母细胞瘤的遗传相互作用。在这里，我们测试了Ku80与细胞周期蛋白激酶抑制剂p27（Kip1）（p27）之间类似的抗肿瘤遗传相互作用，因为p27突变小鼠的垂体腺瘤水平升高，γ辐射诱导的DNA损伤加剧了垂体腺瘤（损伤修复）由Ku80）。我们发现与单个突变体相比，删除Ku80和p27都不会加剧癌症。另外，缺失的成纤维细胞都表现出类似于Ku80突变的成纤维细胞的过早的细胞衰老。因此，p27与Ku80没有明显的遗传相互作用来抑制肿瘤。该观察结果表明，γ射线或Ku80缺失引起的DNA损伤（或DNA损伤反应）并不相同，因为γ射线会加剧缺失p53或p27的小鼠的肿瘤发生，而Ku80缺失只会加剧前一种基因型的肿瘤发生。

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