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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cross-talk between Chk1 and Chk2 in double-mutant thymocytes
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Cross-talk between Chk1 and Chk2 in double-mutant thymocytes

机译：双突变胸腺细胞中Chk1和Chk2之间的串扰

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摘要

Chk1 is a checkpoint kinase and an important regulator of mammalian cell division. Because null mutation of Chk1 in mice is embryonic lethal, we used the Cre-loxP system and the Lck promoter to generate conditional mutant mice in which Chk1 was deleted only in the T lineage. In the absence of Chk1, the transition of CD4~-CD8~- double-negative (DN) thymocytes to CD4~+CD8~+ double-positive (DP) cells was blocked due to an increase in apoptosis at the DN2 and DN3 stages. Strikingly, loss of Chk1 activated the checkpoint kinase Chk2 as well as the tumor suppressor p53 in these thymocytes. However, the developmental defects caused by Chk1 deletion were not rescued by p53 inacti-vation. Significantly, even though Chk1 deletion is highly lethal in proliferating tissues, we succeeded in using in vivo methods to generate Chk1/Chk2 double-knockout T cells. Analysis of these T cells revealed an interesting interaction between Chk1 and Chk2 functions that partially rescued the apoptosis of the double-mutant cells. Thus, Chk1 is both critical for the survival of proliferating cells and engages in cross-talk with the Chk2 checkpoint kinase pathway. These factors have implications for the targeting of Chk1 as an anticancer therapy.
机译：Chk1是检查点激酶，是哺乳动物细胞分裂的重要调节剂。由于Chk1在小鼠中的无效突变是胚胎致死性的，因此我们使用Cre-loxP系统和Lck启动子来产生条件性突变小鼠，其中Chk1仅在T谱系中缺失。在不存在Chk1的情况下，由于DN2和DN3阶段凋亡的增加，阻止了CD4〜-CD8〜-双阴性（DN）胸腺细胞向CD4〜+ CD8〜+双阳性（DP）细胞的过渡。 。令人惊讶的是，Chk1的缺失激活了这些胸腺细胞中的检查点激酶Chk2以及肿瘤抑制因子p53。然而，p53失活不能挽救因Chk1缺失引起的发育缺陷。重要的是，即使Chk1缺失在增殖组织中具有高度致死性，我们还是成功地使用了体内方法生成了Chk1 / Chk2双敲除T细胞。对这些T细胞的分析揭示了Chk1和Chk2功能之间的有趣相互作用，从而部分挽救了双突变细胞的凋亡。因此，Chk1对增殖细胞的生存至关重要，并且与Chk2检查点激酶途径相互作用。这些因素对于将Chk1靶向作为一种抗癌疗法具有影响。

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