Chk1 and Chk2 in Human Cancer Cells

描述（由申请人提供）：许多常用的化疗药物损伤DNA并激活延迟细胞周期进程的检查点。许多类型的癌症在检查点途径中显示出缺陷，这些缺陷被认为是导致遗传不稳定的原因。该提案的总体目标是使用转基因人类细胞来确定激酶Chk 1和Chk 2如何触发检查点以应对各种形式的DNA损伤，以及它们是否具有维持遗传稳定性的功能。目的1是确定Chk 2在癌细胞的治疗敏感性中的作用。由于CHK2基因的突变被认为有助于几种类型的癌症，因此将检查Chk2介导的检查点的缺失是否可以使细胞对抗癌治疗敏感。检查点缺陷被认为有助于基因组的不稳定性，但Chk2如何有助于肿瘤发生仍不清楚。目的2将研究Chk 2在维持遗传稳定性中的作用。目的3是建立一个新的，同基因的人类癌细胞系统，检查的作用，激活的关键Chk1激酶的细胞周期检查点和基因组的稳定性。

DESCRIPTION (provided by applicant): Many commonly used chemotherapeutic drugs damage DNA and activate checkpoints that delay cell cycle progression. Many types of cancer show defects in checkpoint pathways and these defects are thought to contribute to genetic instability. The overall aim of this proposal is to use genetically modified human cells to determine how the kinases Chk1 and Chk2 trigger checkpoints in response to various forms of DNA damage and whether they function to maintain genetic stability. Aim 1 is to determine the role of Chk2 in the therapeutic sensitivity of cancer cells. As mutations of the CHK2 gene are thought to contribute to several types of cancer, whether loss of Chk2-mediated checkpoints can sensitize cells to anticancer therapy will be examined. Checkpoint defects are thought to contribute to genomic instability, but how Chk2 contributes to tumorigenesis remains unclear. Aim 2 will examine the role of Chk2 in maintaining genetic stability. Aim 3 is to create a novel, isogenic human cancer cell system with which to examine the role of activation of the essential Chk1 kinase in cell cycle checkpoints and genomic stability.