UPSTREAM SIGNALS AND DOWNSTREAM TARGETS OF C-AB1

描述：c-Abl是一种非受体酪氨酸激酶，由 某些DNA破坏剂 最近的研究表明，c-Abl 在应激活化蛋白激酶（SAPK，JNK）的上游起作用， 丝裂原活化蛋白激酶（mitogen-activated protein kinase，p38 MAPK）。 其他工作有 显示DNA损伤诱导c-Abl与p53结合，且c-Abl 调节G1期生长停滞反应的遗传毒性压力， p53依赖，p21非依赖机制。 c-Abl的磷酸化 在有丝分裂期间p34 cdc 2的多个位点也支持了这种作用。 G2期蛋白酪氨酸激酶。 因为DNA损伤与 细胞阻滞在G1和G2期，c-Abl激活可能在 调节这些反应和应激途径，包括SAPK和 p38（MAPK）MAPK。 基因毒性应激激活c-Abl的机制 是未知的。 拟议的工作将探讨申请人最近的发现 c-Abl与DNA依赖性蛋白激酶形成核复合物 （DNA-PK）。 DNA-PK与核过程有关，包括 转录、DNA复制和双链DNA断裂修复。 的 Ku自身抗原，DNA-PK催化所必需的DNA末端结合蛋白 活动，招募DNA-PK到DNA。 申请人的初步调查结果 证明DNA损伤诱导c-Abl与 DNA-PK和Ku.该复合物还包括氧化还原蛋白Ref-1。 的 申请人的假设是，这种核复合物有助于 c-Abl的激活和c-Abl调节DNA-PK的诱导 与Ku合作的活动。在拟议工作中获得的结果 应该代表了细胞早期事件研究的范例， 遗传毒性应激反应。

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.