The JNK Signalsome and its Functions

JNK Signalsome 及其功能

• 批准号: 8037653
• 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
• 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/8037653
• 关键词: Affect; Apoptosis; Architecture; Biochemical; Biological Process; Cell Death; Cues; Data; Development; Diabetes Mellitus; Embryonic Development; Event; Genetic; Goals; Health; 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; cancer type; cell transformation; extracellular; human disease; novel; novel strategies; protein complex; response; stress activated protein kinase; tumorigenesis; yeast two hybrid system

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：C-JUN N末端蛋白激酶（JNK；也称为应激激活蛋白激酶，SAPK）在增殖，分化，程序性细胞死亡和转化中起着核心作用。压倒性的证据表明，JNK是许多病理生理事件的关键调节剂，包括炎症，免疫反应，糖尿病，肥胖，心脏肥大和肿瘤发生。然而，仍然尚不完全了解JNK活性受不同细胞外刺激调节的分子机制。在此提案中，我们将研究JNK通过不同的细胞外刺激激活JNK是否由JNK Signalsome介导，这是一种动态蛋白质复合物，其中包括与JNK相关的刺激特异性调节剂或调节剂（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，其活性可以通过刺激特异性调节剂来调节。此外，我们发现两个普遍表达的JNK同工型JNK1和JNK2受到各种细胞外刺激的差异调节。因此，我们假设刺激特异性的JNK信号决定了通过环境刺激和/或胚胎发育提示的JNK激活。该建议是新颖的，因为它将确定JNK} JNK激活的动态和功能性蛋白质复合物，并确定JNK1和JNK2在不同发育阶段差异调节的分子机制。这项研究将提出一个新的范式，涉及通过细胞外刺激来调节JNK有丝分裂原激活蛋白激酶的分子机制，以及针对JNK预防和治疗人类疾病和癌症的JNK方面的基本原理。公共卫生相关性：细胞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，该途径在许多病理生理事件中起着核心作用，并且与许多人类疾病和某些类型的癌症有关。但是，在不影响人类正常生理功能的情况下，很难将JNK靶向JNK。该建议研究了刺激特异性调节剂或调节剂通过特定细胞外刺激来控制JNK激活的分子机制，从而提供了一种新的策略来靶向JNK的独特调节剂或调节剂，而不是JNK本身，以预防和治疗人类疾病和癌症。