Regulation of the cell cycle and signaling by CUL-2 E3 complexes

CUL-2 E3 复合物对细胞周期和信号传导的调节

• 批准号: 8412264
• 负责人: EDWARD T. KIPREOS
• 金额: $ 29.7万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8412264
• 关键词: Actins; Address; Affect; Apoptosis; Autacoids; Binding; Bypass; CDC2 Protein Kinase; Caenorhabditis elegans; Candidate Disease Gene; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell division; Cell physiology; Cells; Complex; Coupled; Cullin 2 Protein; Cullin Proteins; Cyclin B; Cytoplasm; Cytoskeleton; Development; Developmental Process; Disseminated Malignant Neoplasm; Down-Regulation; Endocytosis; Family; Future; Genetic; Genetic Screening; Human; Link; Malignant Neoplasms; Mammals; Mediating; Meiosis; Mitosis; Mitotic; Molecular; Neoplasm Metastasis; Notch Signaling Pathway; Oncogenes; Pathway interactions; Pattern; Penetrance; Phenotype; Post-Translational Protein Processing; Process; Proteins; Regulation; Reporter; Role; Signal Pathway; Signal Transduction; Transgenes; Vulva; base; beta catenin; cancer therapy; cell growth; cell motility; genetic analysis; inhibitor/antagonist; insight; link protein; multicatalytic endopeptidase complex; mutant; notch protein; outcome forecast; precursor cell; protein complex; protein degradation; research study; ribosomal protein S6 kinase 1; ubiquitin ligase

DESCRIPTION (provided by applicant): Cullin 2-RING ubiquitin ligase (CRL2) complexes target proteins for degradation to control dynamic cellular processes including the cell cycle, polarity, and signal transduction. This proposal focuses on understanding the molecular pathways that regulate how CRL2 complexes control: the actin cytoskeleton and cell motility; the Ras and Notch signaling pathways; and the mitotic regulator cyclin B. These CRL2-regulated pathways have important implications for the control of cell proliferation, development, and cancer. Aim 1 focuses on CRL2-mediated regulation of the CDK-inhibitors p21Cip1 and p27Kip2 in the cytoplasm. CRL2LRR1 targets the degradation of cytoplasmic p21 to control actin cytoskeletal dynamics and cell motility. Proposed experiments address the regulation of p21 binding to CRL2LRR1, and the mechanism by which certain oncogenes circumvent CRL2LRR1-mediated degradation of p21. A distinct CRL2 complex regulates cytoplasmic p27 levels through an indirect mechanism by negatively regulating the levels of the Ras pathway effectors RSK1 and RSK2. Experiments address how the degradation of RSK1/2 is regulated; the functional consequences of the degradation; and the identification of the substrate-recognition subunit for the CRL2 complex. Aim 2 seeks to identify the molecular pathway by which CRL2LRR-1 represses Notch signaling in the developing C. elegans vulva, through the use of genetic analysis in combination with reporter transgenes. Aim 3 focuses on the paradigm-shifting observation that the mitotic regulator cyclin B is targeted for degradation not only by the APC/C complex (which is currently regarded as the sole ubiquitin ligase for cyclin B degradation) but also by the CRL2ZYG-11 complex. The cyclin B-CDK1 complex is the key cell cycle regulator that drives cells into mitosis; and the degradation of cyclin B is essential for mitotic exit. Discovering how the degradation of cyclin B is regulated is critical for understandin the overall regulation of mitosis. The experiments in this aim will characterize the interaction of cyclin B with CRL2ZYG-11, determine the mechanism through which the degradation is cell cycle regulated, and explore whether the pathway is conserved in mammals. PUBLIC HEALTH RELEVANCE: Metastatic cancer is caused by the unregulated proliferation of cells that are able to move throughout the body. This proposal addresses how CRL2 protein complexes (which degrade other proteins) act to: inhibit the Ras and Notch signaling pathway that promote cancer; block cell movements; and degrade a central regulator of cell division (cyclin B). This project will provide new insights into fundamental cancer-related processes, and provide the potential for the future development of cancer therapies.

描述（由申请人提供）：Cullin 2环泛素连接酶（CRL2）复合物靶蛋白降解以控制动态细胞过程，包括细胞周期，极性和信号转导。该建议着重于理解调节CRL2复合物如何控制的分子途径：肌动蛋白细胞骨架和细胞运动。 RAS和Notch信号通路；和有丝分裂调节剂细胞周期蛋白B。这些CRL2调节的途径对控制细胞增殖，发育和癌症具有重要意义。 AIM 1专注于细胞质中CDK抑制剂P21CIP1和P27KIP2的CRL2介导的调节。 CRL2LRR1靶向细胞质p21的降解以控制肌动蛋白细胞骨架动力学和细胞运动。提出的实验涉及P21与CRL2LRR1结合的调节，以及某些发病基因绕过p21的CRL2LRRR1介导的降解的机制。不同的CRL2复合物通过间接机制来调节细胞质P27水平，通过负调节RAS途径效应子RSK1和RSK2的水平。实验介绍了如何调节RSK1/2的降解；降解的功能后果；以及CRL2复合物的底物 - 识别亚基的鉴定。 AIM 2试图通过将遗传分析与记者转基因结合使用遗传分析来识别CRL2LRR-1在发育中的秀丽隐杆线外阴中抑制Notch信号传导的分子途径。 AIM 3的重点是范式转移观察，即有丝分裂调节剂Cyclin B不仅是APC/C复合物（目前被视为Cyclin b降解的唯一泛素连接酶）的降解，而且还由CRL2ZYG-111复合物进行降解。细胞周期蛋白B-CDK1复合物是将细胞转化为有丝分裂的关键细胞周期调节剂。细胞周期蛋白B的降解对于有丝分裂出口至关重要。发现细胞周期蛋白B的降解如何调节对于了解有丝分裂的整体调节至关重要。此目标的实验将表征 用CRL2ZYG-11的细胞周期蛋白B确定降解受细胞周期调节的机制，并探索该途径是否在哺乳动物中保守。 公共卫生相关性：转移性癌症是由能够在整个体内移动的细胞的不受管制的增殖引起的。该提案解决了CRL2蛋白复合物（降解其他蛋白质）的作用：抑制促进癌症的RAS和Notch信号传导途径；阻止细胞运动；并降解细胞分裂的中央调节剂（Cyclin B）。该项目将为与癌症相关的基本过程提供新的见解，并为癌症疗法的未来发展提供潜力。