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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氨基末端蛋白激酶(JNK；又称应激激活蛋白激酶，SAPK)在细胞的增殖、分化、程序性死亡等过程中起核心作用和转型。压倒性的证据表明，JNK是许多病理生理事件，包括炎症、免疫反应、糖尿病、肥胖、心脏肥大和肿瘤发生。然而，分子机制是通过哪些JNK活性受不同的细胞外刺激调节仍不完全明白了。在这项提案中，我们将调查JNK是否通过DISTINCT激活细胞外刺激由JNK信号体介导，JNK信号体是一种动态蛋白质包括JNK相关的、刺激特定的调节器或调节器的复合体 (SMOR)。使用遗传和生化方法，我们最近发现JNK 形成一种蛋白质复合体，其活性可由刺激特异性调节剂调节。此外，我们还发现了两种普遍表达的JNK亚型，JNK1和JNK2，受到不同的细胞外刺激的差异调节。因此，我们假设刺激特异性JNK信号决定环境刺激对JNK的激活和/或胚胎发育线索。这一建议是新颖的，因为它将确定JNK信号的一些动态和功能蛋白复合体对JNK的激活，并确定其分子机制其中JNK1和JNK2在不同发育阶段受到不同的调控。这项研究将提出一种关于分子机制的新范式 JNK丝裂原活化蛋白激酶亚家族的调控细胞外刺激及以JNK为靶点防治白血病的理论基础人类疾病和癌症。项目叙事细胞信号网络由许多重要的信号通路组成，包括应激激活蛋白激酶JNK途径，它在许多病理生理事件，并与许多人类疾病和某些类型的癌症。然而，以JNK为靶点用于治疗是困难的而不影响人体的正常生理功能。这项建议研究了刺激特异性调节子或调节子控制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靶向 JNK的独特调节器或调节器，而不是JNK本身，用于预防和治疗人类疾病和癌症。