Perona Rosario, Moncho-Amor Verónica, Machado-Pinilla Rosario, Belda-Iniesta Cristóbal, Sánchez Pérez Isabel
Instituto de Investigaciones Biomédicas C.S.I.C./U.A.M., Madrid, Spain.
Clin Transl Oncol. 2008 Sep;10(9):538-42. doi: 10.1007/s12094-008-0248-5.
DNA repair pathways enable tumour cells to survive DNA damage induced by external agents such as therapeutic treatments. Signalling cascades involved in these pathways comprise the DNA-dependent protein kinase (DNA-PK), Ataxia-telangiectasia mutated (ATM), ATM and Rad3 related (ATR) and checkpoint kinases I and 2 (Chk1/Chk2), among others. ATM and ATR phosphorylate, respectively, Chk2 and Chk1, leading to activation of checkpoints. Chk2 acts as a signal distributor, dispersing checkpoint signal to downstream targets such as p53, Cdc25A, Cdc25C, BRCA1 and E2F1. A role of Chk2 as a candidate tumour suppressor has been suggested based on both mouse genetics and somatic tumour studies. We will discuss here the possible role of this kinase in human carcinogenesis and the possibility to use it as a target to increment DNA damage in cancer cells in response to DNA-damaging therapies.
DNA修复途径使肿瘤细胞能够在诸如治疗性处理等外部因素诱导的DNA损伤中存活。参与这些途径的信号级联包括DNA依赖性蛋白激酶（DNA-PK）、共济失调毛细血管扩张症突变蛋白（ATM）、ATM和Rad3相关蛋白（ATR）以及检查点激酶1和2（Chk1/Chk2）等。ATM和ATR分别使Chk2和Chk1磷酸化，从而导致检查点的激活。Chk2作为信号分配器，将检查点信号分散到下游靶点，如p53、Cdc25A、Cdc25C、BRCA1和E2F1。基于小鼠遗传学和体细胞肿瘤研究，有人提出Chk2作为候选肿瘤抑制因子的作用。我们将在此讨论这种激酶在人类致癌过程中的可能作用，以及将其用作靶点以增加癌细胞对DNA损伤疗法的DNA损伤的可能性。
