Chk1 and Chk2 in Human Cancer Cells

描述（由申请人提供）：许多常用的化疗药物会损伤DNA并激活延迟细胞周期进展的检查点。许多类型的癌症在检查点通路中显示出缺陷，这些缺陷被认为是导致遗传不稳定的原因。这项提议的总体目标是使用转基因人类细胞来确定Chk1和Chk2激酶如何触发检查点以响应各种形式的DNA损伤，以及它们是否起作用以维持遗传稳定性。目的1是确定Chk2在癌细胞治疗敏感性中的作用。由于CHK2基因的突变被认为与几种类型的癌症有关，因此CHK2介导的检查点的丢失是否可以使细胞对抗癌治疗敏感将被研究。检查点缺陷被认为有助于基因组不稳定，但Chk2如何促进肿瘤发生尚不清楚。目的2将研究Chk2在维持遗传稳定性中的作用。目的3是创建一个新的，等基因的人类癌细胞系统，用它来检查必需的Chk1激酶的激活在细胞周期检查点和基因组稳定性中的作用。

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.