Yang Jun, Yu Yingnian, Hamrick Hope E, Duerksen-Hughes Penelope J
Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310031, China.
Carcinogenesis. 2003 Oct;24(10):1571-80. doi: 10.1093/carcin/bgg137. Epub 2003 Aug 14.
Exposure to genotoxic agents is a major cause of human cancer, and cellular responses to genotoxic stress are important defense mechanisms. These responses are very complex, involving many cellular factors that form an extensive signal transduction network. This network includes a protein kinase cascade that connects the detection of DNA damage to the activation of transcription factors, which in turn regulate the expression of genes involved in DNA repair, cell cycle arrest and programmed cell death (apoptosis). The mitogen-activated protein kinases are the best-studied members of the kinase cascade with an acknowledged role in the genotoxic stress response. However, the initial activation of the protein kinase cascade is not fully understood, although several protein kinases, such as ataxia telangiectasia, mutated (ATM), ATM- and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK) in humans, are increasingly recognized for their potential roles in the sensing of DNA damage and initiating the subsequent protein kinase cascade. In this review, the properties of these three kinases are discussed and their functions in the initiation of the genotoxic stress response are explored.
接触基因毒性剂是人类癌症的主要原因，细胞对基因毒性应激的反应是重要的防御机制。这些反应非常复杂，涉及许多形成广泛信号转导网络的细胞因子。该网络包括一个蛋白激酶级联反应，它将DNA损伤的检测与转录因子的激活联系起来，而转录因子又反过来调节参与DNA修复、细胞周期停滞和程序性细胞死亡（凋亡）的基因的表达。丝裂原活化蛋白激酶是激酶级联反应中研究得最透彻的成员，在基因毒性应激反应中具有公认的作用。然而，尽管人类中的几种蛋白激酶，如共济失调毛细血管扩张症突变型（ATM）、ATM和Rad3相关蛋白（ATR）以及DNA依赖性蛋白激酶（DNA-PK），因其在检测DNA损伤和启动后续蛋白激酶级联反应中的潜在作用而越来越受到认可，但蛋白激酶级联反应的初始激活仍未完全了解。在这篇综述中，将讨论这三种激酶的特性，并探讨它们在启动基因毒性应激反应中的功能。
