Kharbanda S, Yuan Z M, Weichselbaum R, Kufe D
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Oncogene. 1998 Dec 24;17(25):3309-18. doi: 10.1038/sj.onc.1202571.
The cellular response to DNA damage includes growth arrest and activation of DNA repair. Certain insights into how DNA damage is converted into intracellular signals that control the genotoxic stress response have been derived from the finding that the c-Abl protein tyrosine kinase is activated by ionizing radiation and other DNA-damaging agents. c-Abl associates with the DNA-dependent protein kinase (DNA-PK) and is activated by DNA-PK-dependent phosphorylation. The ataxia telangiectasia mutated (ATM) gene product also contributes to c-Abl activation. The demonstration that c-Abl binds to p53, induces the transactivation function of p53 and activates p21 expression has supported involvement of c-Abl in regulation of the p53-dependent G1 arrest response. Interaction between c-Abl and the Rad51 protein has also provided support for involvement of c-Abl in recombinational repair of DNA strand breaks. Defects in G1 arrest and repair predispose to replication of damaged templates and, in the event of irreparable DNA lesions, induction of apoptosis. The available evidence indicates that c-Abl effects a proapoptotic function by a mechanism largely independent of p53. c-Abl also functions as an upstream effector of the proapoptotic JNK/SAPK and p38 MAPK pathways. In addition, c-Abl-dependent inhibition of PI 3-kinase contributes to the induction of apoptosis. The findings thus suggest that, in response to genotoxic stress, c-Abl functions in determining cell fate, that is growth arrest and repair or induction of apoptosis. The physiologic function of c-Abl may reside in control of the cellular response to DNA strand breaks that occur during DNA replication, genetic recombination and gene rearrangements.
细胞对DNA损伤的反应包括生长停滞和DNA修复的激活。关于DNA损伤如何转化为控制基因毒性应激反应的细胞内信号，已从以下发现中获得了一些见解：c-Abl蛋白酪氨酸激酶可被电离辐射和其他DNA损伤剂激活。c-Abl与DNA依赖性蛋白激酶（DNA-PK）结合，并通过DNA-PK依赖性磷酸化被激活。共济失调毛细血管扩张症突变（ATM）基因产物也有助于c-Abl的激活。c-Abl与p53结合、诱导p53的反式激活功能并激活p21表达的证明，支持了c-Abl参与p53依赖性G1期停滞反应的调控。c-Abl与Rad51蛋白之间的相互作用也为c-Abl参与DNA链断裂的重组修复提供了支持。G1期停滞和修复缺陷易导致受损模板的复制，并且在发生无法修复的DNA损伤时，会诱导细胞凋亡。现有证据表明，c-Abl通过一种很大程度上独立于p53的机制发挥促凋亡功能。c-Abl还作为促凋亡JNK/SAPK和p38 MAPK途径的上游效应物发挥作用。此外，c-Abl依赖性对PI 3激酶的抑制作用也有助于诱导细胞凋亡。因此，这些发现表明，在对基因毒性应激的反应中，c-Abl在决定细胞命运（即生长停滞、修复或诱导凋亡）方面发挥作用。c-Abl的生理功能可能在于控制细胞对DNA复制、基因重组和基因重排过程中发生的DNA链断裂的反应。
