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首页> 外文期刊>Cell cycle >14-3-3sigma and p21 synergize to determine DNA damage response following Chk2 inhibition.
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14-3-3sigma and p21 synergize to determine DNA damage response following Chk2 inhibition.

机译：14-3-3sigma和p21协同确定Chk2抑制后的DNA损伤反应。

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摘要

DNA damage checkpoints are critical for preventing tumorigenesis and regulating the response of cells to genotoxic agents. It is believed that the coordinated actions of a number of effectors underlie proper checkpoint function. The kinase Chk2, p21 and 14-3-3sigma have each been shown to be independent effectors of the G(2) DNA damage checkpoint. However, the relative roles of these proteins remain unclear. To help elucidate this question, we have perturbed each of these 3 genes in combination in human cells. We show that Chk2 depletion causes markedly increased sensitivity to DNA damage in p21(-/-), 14-3-3sigma(-/-) cells but not in cells lacking only one or none of these genes. This greater sensitivity was due to an increase in apoptosis following DNA damage and not due to exacerbation of G(2) checkpoint defects. Pharmacologic inhibition of Chk2 in p21(-/-), 14-3-3sigma(-/-) cells also resulted in greater sensitivity to DNA damage. Our data indicates that p21 and 14-3-3sigma synergize as molecular determinants of sensitivity to DNA damage following Chk2 inhibition, and Chk2 modulates the biological rheostat that determines whether a cancer cell undergoes arrest versus death after treatment with a chemotherapeutic agent. These findings have implications for the targeting of Chk2 in human cancers.
机译：DNA损伤检查点对于预防肿瘤发生和调节细胞对遗传毒性剂的反应至关重要。据信，许多效应子的协调作用是适当检查点功能的基础。激酶Chk2，p21和14-3-3sigma已被证明分别是G（2）DNA损伤检查点的独立效应子。但是，这些蛋白的相对作用仍不清楚。为了阐明这个问题，我们在人体细胞中结合了这3个基因中的每一个。我们显示，Chk2耗竭导致p21（-/-），14-3-3sigma（-/-）细胞对DNA损伤的敏感性显着增加，但在缺少这些基因之一或没有这些基因的细胞中却没有。这种更大的敏感性是由于DNA损伤后细胞凋亡的增加，而不是由于G（2）检查点缺陷的恶化。在p21（-/-），14-3-3sigma（-/-）细胞中Chk2的药理抑制作用还导致对DNA损伤的敏感性更高。我们的数据表明，p21和14-3-3sigma协同作用是对Chk2抑制后对DNA损伤的敏感性的分子决定因素，并且Chk2调节生物变阻器，该变阻器确定癌细胞在接受化学治疗剂后是否会停滞而死亡。这些发现对在人类癌症中靶向Chk2具有重要意义。

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