THE STRESS-ACTIVATED PROTEIN KINASE PATHWAY

描述（改编自申请人的摘要）：应激激活的细胞 信号转导机制在肿瘤的发病机制中起着重要作用。 几个重要的临床症状。包括缺血性损伤（如发生在 心脏病发作和中风），关节炎，脓毒性休克，以及 放疗和化疗应激激活蛋白激酶（SAPKs，也称为 称为JNK）和p38是促分裂活化蛋白激酶（MAPK）亚类 负责激活激活蛋白-1（AP-1） 转录因子复合体对环境胁迫的应答， 炎性细胞因子TNF和IL-1。与核因子-kB一起 （NF-kB）途径，SAPKs和p38代表应激的主要机制， 炎症诱导的基因表达。与所有MAPK途径一样，SAPKs和 p38本身作为MAPK-激酶-激酶（MAP 3 K）的一部分被调节。 MAPK-激酶（MEK）-> MAPK核心信号分子。虽然许多这样的潜力 核心模块已被确定，这些调控的分子基础 尽管解剖MAP 3 K， 调节是理解这些细胞的生理作用的关键。 途径。这一正在进行的项目的下一阶段将侧重于 两种应激激活的MAP 3 Ks的调节：MEK-激酶（MEKK）-1和凋亡 信号调节激酶-1（ASK 1），通过与TNF受体偶联的元件 （TNFR）复合物。首席研究员正在进行的研究表明， MEKK 1受生发中心激酶-1（GCK）调节，GCK是MEKK 1的一种假定效应子。 肿瘤坏死因子受体相关因子-1（TRAF 2）。研究人员的研究还 支持ASK 1是TRAf 2的潜在效应子的论点。他将利用 通过体外和体内生物化学方法来表征该机制， 其中TRAF 2调节观察到的GCK 1和MEKK 1之间的体内结合。 他将使用生物化学和细胞生物学方法来确定MEKK 1是否是 由GCK 1和/或TRAF 2介导的寡聚化激活。最后，他会 使用体外和体内生物化学方法来确定ASK 1是否受到调节 通过抑制蛋白硫氧还蛋白的解离和聚集介导的 关于TRAF 2这些研究将进一步阐明哺乳动物应激信号 途径，并有助于识别新的抗炎药 目标和治疗策略。

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.