THE STRESS-ACTIVATED PROTEIN KINASE PATHWAY

描述(摘自申请者摘要)：应激激活的细胞 信号转导机制在糖尿病的发病机制中起着重要作用。 几种重要的临床症状。包括缺血性损伤(发生在 心脏病发作和中风)，关节炎，感染性休克，以及 放疗和化疗。应激激活蛋白激酶(SAPKs) 和p38是丝裂原活化蛋白激酶(MAPK)亚群 负责激活蛋白-1(AP-1)的激活 转录因子复合体对环境胁迫的响应和 炎性细胞因子肿瘤坏死因子和白介素1。与核因子-kB一起 (NF-kB)途径，SAPKs和P38S是应激的主要机制-和 炎症诱导的基因表达。与所有MAPK途径一样，SAPKs和 P38S本身作为MAPK-Kinase-Kinase(MAP3K)-&GT的一部分进行调节； MAPK-激酶(MEK)-&GT；MAPK核心信号分子。虽然许多这样的潜力 核心模块已经被确定，调控这些的分子基础 尽管解剖MAP3K的事实仍然不清楚 调节对于理解这些细胞的生理作用至关重要。 小路。这个正在进行的项目的下一阶段将专注于 两种应激激活的MAP3K：MEK-K(MEKK)-1的调节与细胞凋亡 与肿瘤坏死因子受体偶联的信号调节蛋白-1(ASK1) (TNFR)复合体。首席调查员正在进行的研究表明 MEKK1受生发中心激酶-1(GCK)的调节，GCK是一种可能的效应因子 肿瘤坏死因子受体相关因子1(TRAF2)。调查员的研究也 支持ASK1是TRAf2的潜在效应者的观点。他将使用 通过体外和体内生化方法研究其作用机制 其中TRAF2调节GCK1和MEKK1之间的体内联系。 他将使用生化和细胞生物学方法来确定MEKK1是否 由GCK1和/或TRAF2介导的齐聚激活。最后，他会 用体外和体内生化方法确定ASK1是否受调控 通过解离一种抑制蛋白硫氧还蛋白和介导的聚集 通过TRAF2。这些研究将进一步阐明哺乳动物的压力信号。 新型抗炎药物的鉴定途径和贡献 靶点和治疗策略。

DESCRIPTION (adapted from applicant's abstract): Stress-activated cellular signal transduction mechanisms play a significant part in the pathogenesis of several important clinical conditions. Including ischemic injury (as occurs in heart attack and stroke), arthritis, septic shock, and the side effects of radiation and chemotherapy. The stress-activated protein kinases (SAPKs, also called JNKs) and p38 are mitogenic-activated protein kinase (MAPK) subgroups that are responsible for the activation of the activator protein-1 (AP-1) transcription factor complex in response to environmental stress and the inflammatory cytokines TNF and IL-1. Together with the nuclear factor-kB (NF-kB) pathway, the SAPKs and p38s represent major mechanisms of stress- and inflammation-induced gene expression. As with all MAPK pathways, the SAPKs and p38s are themselves regulated as part of MAPK-kinase-kinase (MAP3K) -> MAPK-kinase (MEK) -> MAPK core signaling molecules. While many such potential core modules have been identified, molecular basis for the regulation of these pathways has remained unclear in spite of the fact that dissecting MAP3K regulation is pivotal to the understanding of the physiologic roles of these pathways. The next phase of this on going project will be to focus on the regulation of two stress-activated MAP3Ks:MEK-kinase (MEKK)-1 and apoptosis signal-regulating kinase-1 (ASK1), by elements coupled to the TNF receptor (TNFR) complex. The principal investigator's ongoing studies indicate that MEKK1 is regulated by germinal center kinase-1 (GCK), a putative effector for TNF receptor-associated factor-1 (TRAF2). The investigator's studies also support the contention that ASK1 is a potential effector for TRAf2. He will use in vitro and in vivo biochemical methods to characterize the mechanism by which TRAF2 regulates the observed in vivo association between GCK1 and MEKK1. He will use biochemical and cell biological methods to determine if MEKK1 is activated by oligomerization mediated by GCK1 and or TRAF2. Finally, he will use in vitro and in vivo biochemical methods to determine if ASK1 is regulated by dissociation of an inhibitor protein, thioredoxin, and aggregation mediated by TRAF2. These studies will clarify further mammalian stress signaling pathways and contribute to the identification of novel anti-inflammatory drug targets and therapeutic strategies.