UPSTREAM SIGNALS AND DOWNSTREAM TARGETS OF C-AB1

点击翻译按钮获取中文摘要

DESCRIPTION: c-Abl is a nonreceptor tyrosine kinase that is activated by certain DNA-damaging agents. Recent studies have demonstrated that c-Abl functions upstream of the stress-activated protein kinase (SAPK, JNK) and the p38(MAPK) mitogen-activated protein kinase (p38 MAPK). Other work has shown that DNA damage induces binding of c-Abl to p53 and that c-Abl regulates the G1 growth arrest response to genotoxic stress by a p53-dependent, p21-independent mechanism. Phosphorylation of c-Abl at multiple sites by p34cdc2 during mitosis has also supported a role for this protein tyrosine kinase in G2 phase. Because DNA damage is associated with arrest of cells in G1 and G2 phases, c-Abl activation may play a role in regulating these responses and in stress pathways that include SAPK and p38(MAPK) MAPK. The mechanism responsible for the activation of c-Abl by genotoxic stress are unknown. The proposed work will explore the applicant's recent finding that c-Abl forms a nuclear complex with the DNA-dependent protein kinase (DNA-PK). DNA-PK has been implicated in nuclear processes including transcription, DNA replication, and double-stranded DNA break repair. The Ku autoantigen, a DNA end-binding protein necessary for DNA-PK catalytic activity, recruits DNA-PK to DNA. The applicant's preliminary findings demonstrate that DNA damage induces the formation of a complex of c-Abl with DNA-PK and Ku. This complex also includes the redox protein Ref-1. The applicant's hypothesis is that this nuclear complex contributes to the activation of c-Abl and that c-Abl regulates the induction of DNA-PK activity by associating with Ku. The findings obtained in the proposed work should represent a paradigm for studies on early events in the cellular response to genotoxic stress.