Chk1 and Chk2 in Human Cancer Cells

描述(由申请人提供)：许多常用的化疗药物破坏DNA并激活检查点，延缓细胞周期进展。许多类型的癌症在检查点通路上表现出缺陷，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激酶Chk1和Chk2如何触发检查点，以应对各种形式的DNA损伤，以及它们是否起到维持遗传稳定的作用。目的1确定Chk2在肿瘤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会使细胞对抗癌治疗敏感，将进行检查。检查点缺陷被认为是基因组不稳定的原因，但Chk2如何促进肿瘤发生仍不清楚。目标2将研究Chk2在维持遗传稳定性中的作用。目的3是创建一种新的、等基因的人类癌细胞系统，用来检测必要的Chk1激酶在细胞周期检查点和基因组稳定性中的激活作用。

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.