UPSTREAM SIGNALS AND DOWNSTREAM TARGETS OF C-AB1

描述：C-Abl是一种非受体酪氨酸激酶，由 某些破坏DNA的毒剂。最近的研究表明，c-Abl 应激激活蛋白激酶(SAPK，JNK)上游的功能和 P38(MAPK)丝裂原活化蛋白激酶(P38MAPK)。其他工作也有 DNA损伤诱导c-Abl与P53结合，c-Abl 通过一种途径调节对遗传毒性应激的G1生长抑制反应 P53依赖、p21不依赖的机制。C-Abl at的磷酸化 P34cdc2在有丝分裂过程中的多个位点也支持这一作用 蛋白酪氨酸激酶处于G2期。因为DNA损伤与 细胞停滞于G1期和G2期，c-Abl激活可能在 调节这些反应以及在包括SAPK和SAPK在内的应激途径中 P38(MAPK)MAPK。 基因毒性应激激活c-Abl的机制 都是未知的。这项拟议的工作将探索申请人的最新发现 C-Abl与DNA依赖的蛋白激酶形成核复合体 (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。这个 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c-Abl形成复合体 DNA-PK和Ku。该复合体还包括氧化还原蛋白Ref-1。这个 申请人的假设是，这个核复合体有助于 C-Abl激活及c-Abl调控DNA-PK的诱导 通过与Ku的交往来进行活动。在拟议工作中获得的结果 应该代表了细胞内早期事件研究的范例 对基因毒性应激的反应。

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.