The JNK Signalsome and its Functions

JNK Signalsome 及其功能

基本信息

批准号：
8231495
负责人：
JING LIU
金额：
$ 28.12万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8231495
关键词：
Affect Apoptosis Architecture Biochemical Biological Process Cell Death Cues Data Development Diabetes Mellitus Embryonic Development Event Genetic Goals Heart Hypertrophy Human Immune response Inflammation JUN gene Knock-out MAPK8 gene MAPK9 gene Malignant Neoplasms Mediating Mitogen-Activated Protein Kinase Kinases Molecular N-terminal Obesity Pathway interactions Phosphorylation Phosphotransferases Physiological Play Prevention Protein Isoforms Protein Kinase Proteins Recruitment Activity Regulation Research Role SAPK Screening procedure Signal Pathway Signal Transduction Staging Stimulus Stress TNF gene TRAF2 gene Therapeutic Ubiquitination Yeasts Zinc Fingers abstracting cancer type cell transformation extracellular human disease novel novel strategies protein complex response stress activated protein kinase tumorigenesis yeast two hybrid system

项目摘要

Project Summary/Abstract c-Jun N-terminal protein kinase (JNK; also known as stress-activated protein kinase, SAPK) plays a central role in proliferation, differentiation, programmed cell death and transformation. Overwhelming evidence implicates that JNK is a key regulator in many pathophysiological events including inflammation, immune responses, diabetes, obesity, heart hypertrophy, and oncogenesis. However, the molecular mechanism by which JNK activity is regulated by distinct extracellular stimuli is still incompletely understood. In this proposal, we will investigate whether JNK activation by distinct extracellular stimuli is mediated by a JNK signalsome, which is a dynamic protein complex that includes JNK-associated, stimulus-specific modulators or regulators (SMOR). Using both genetic and biochemical approaches, we recently found that JNK forms a protein complex and its activity can be regulated by stimulus-specific regulators. Furthermore, we found that two ubiquitously expressed JNK isoforms, JNK1 and JNK2, are differentially regulated by various extracellular stimuli. Thus, we hypothesize that the stimulus-specific JNK signalsome determines JNK activation by environmental stimuli and/or embryonic development cues. This proposal is novel, as it will identify the JNK signalsome ¿ a dynamic and functional protein complex for JNK activation, and determine the molecular mechanisms by which JNK1 and JNK2 are differentially regulated at different developmental stages. This study will put forward a novel paradigm regarding the molecular mechanism underlying the regulation of the JNK mitogen-activated protein kinase subfamily by extracellular stimuli and the rationale in targeting JNK for prevention and treatment of human diseases and cancer. Project Narrative The cell signaling network is composed of many important signaling pathways, including the stress activated protein kinase JNK pathway, which plays a central role in many pathophysiological events and has been implicated in numerous human diseases and certain types of cancer. However, it is difficult to target JNK for therapeutic purposes without affecting normal physiological functions in human. This proposal studies the molecular mechanism by which stimulus-specific modulators or regulators control JNK activation by specific extracellular stimuli, thereby providing a novel strategy to target the unique modulators or regulators of JNK, rather than JNK itself, for prevention and treatment of human diseases and cancer.

项目摘要/摘要 C-JUN N末端蛋白激酶（JNK；也称为应激激活蛋白激酶，SAPK）在扩散，分化，程序性细胞死亡中起着核心作用和转型。压倒性的证据暗示JNK是关键的调节器许多病理生理事件，包括炎症，免疫调查，糖尿病，肥胖，心脏肥大和肿瘤发生。但是，通过哪些JNK活性由不同的细胞外刺激调节理解。在此提案中，我们将调查JNK是否通过不同的细胞外刺激是由JNK信号介导的，这是一种动态蛋白包括JNK相关的，刺激特异性调节器或调节器的复合物（Smor）。使用遗传和生化方法，我们最近发现JNK 形成蛋白质复合物及其活性可以通过刺激特异性调节剂调节。此外，我们发现两个无处不在的JNK同工型JNK1和JNK2，通过各种细胞外刺激对不同的调节。那我们假设刺激特异性的JNK信号决定了通过环境刺激的JNK激活和/或胚胎开发提示。该建议是新颖的，因为它将确定JNK明显 JNK激活的功能蛋白复合物，并确定分子机制 JNK1和JNK2在不同的发育阶段受到不同调节。这项研究将提出有关分子机制的新型范式基础JNK促丝分裂原激活蛋白激酶亚科的调节细胞外刺激和靶向JNK预防和治疗的基本原理人类疾病和癌症。项目叙述电池信号网络由许多重要的信号通路组成，包括应力激活的蛋白激酶JNK途径，在许多人中起着核心作用病理生理事件，已在许多人类疾病中隐含某些类型的癌症。但是，很难将JNK靶向治疗目的不影响人类正常的生理功能。该提议研究了刺激特异性调节器或调节器控制JNK的分子机制通过特定的细胞外刺激激活，从而提供了一种新的策略来靶向 JNK的独特调节器或监管机构，而不是JNK本身用于预防和治疗人类疾病和癌症。