Regulation of the cell proliferation by CRL ubiquitin ligases

CRL 泛素连接酶对细胞增殖的调节

• 批准号: 10379088
• 负责人: MICHELE PAGANO
• 金额: $ 33.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379088
• 关键词: Area; Autophagocytosis; Biochemical; Biological; Biological Process; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation Regulation; Cell physiology; Cells; Clinical; Communicable Diseases; Complex; Cullin Proteins; DNA Damage; DNA Repair; Dimensions; Enzymes; Etiology; Genetic; Goals; Immunomodulators; Laboratories; Lead; Life; Light; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Metabolic Diseases; Molecular; Neurodegenerative Disorders; New Territories; Oncology; Play; Process; Proteomics; Regulation; Research; Role; Signal Transduction; Signal Transduction Pathway; Sleep Disorders; System; Thalidomide; Ubiquitin; circadian pacemaker; field study; human disease; in vivo; insight; interdisciplinary approach; interest; multicatalytic endopeptidase complex; novel therapeutic intervention; response; success; ubiquitin ligase

PROJECT ABSTRACT / SUMMARY More than 30 years have passed since the discovery of the ubiquitin-proteasome system, yet we still lack comprehensive insights into its regulatory mechanisms. This limitation arises because most of the approximately 600 ubiquitin ligase enzymes in mammals remain largely uncharacterized. Our laboratory has focused on how Cullin-RING Ubiquitin Ligase (CRL) complexes control the three essential dimensions of cellular life: proliferation, survival, and differentiation. We have played a central role in elucidating how, when, where and, most importantly, why CRLs mediate the degradation of key cellular regulators. The research in my laboratory initially focused on the paradigm of the timed regulation of the mammalian cell cycle by the ubiquitin-proteasome system, which we established a number of years ago. We have since expanded our research into five fields of study: (i) cell signaling, (ii) cell cycle control, (iii) the DNA damage response, (iv) oncology, and (v) the circadian clock. This expansion of our interests has been possible thanks to our discovery-driven approach that, in contrast to the more common hypothesis-driven approach, is unbiased. Yet, the results of genetics and proteomics screens are not our end goal, but they guide us to explain the underlying biological concepts and mechanisms. Importantly, they often lead us to unexpected and unexplored new territories, opening our horizons. In summary, we use a comprehensive and interdisciplinary approach to break new grounds and make transformative discoveries that will provide new mechanistic insights into fundamental biological processes, particularly those processes that are regulated by CRLs. The current proposed research will cover all the mechanistic studies performed in our laboratory concerning areas i-iii listed above. In particular, we will leverage our recognized expertise in the ubiquitin field to discover molecular mechanisms by which CRLs control signal transduction pathways, autophagy, cell cycle progression, and DNA repair. Moreover, we will perform biochemical, cellular and in vivo analyses to illuminate how CRLs are regulated to function as switches between diverse cell fates. These findings will substantially advance our understanding of the proper execution of crucial cellular processes, potentially shedding light on the etiologies and treatments of human diseases.

项目摘要/总结 自发现泛素-蛋白酶体系统以来，已经过去了30多年，然而， 我们仍然缺乏对其监管机制的全面了解。这种局限性产生于 因为哺乳动物中大约600种遍在蛋白连接酶中的大多数大部分 没有特征的我们的实验室专注于Cullin-RING泛素连接酶（CRL） 复合体控制着细胞生命的三个基本方面：增殖，存活， 分化我们在阐明如何、何时、何地和最 重要的是，为什么CRL介导关键细胞调节因子的降解。在我的研究 一个实验室最初专注于哺乳动物细胞周期的定时调节模式 由我们几年前建立的泛素-蛋白酶体系统。我们有 从那时起，我们的研究扩展到五个研究领域：（i）细胞信号，（ii）细胞周期控制，（iii） DNA损伤反应，（iv）肿瘤学，和（v）生物钟。我们的扩张 由于我们以发现为导向的方法， 更常见的假设驱动的方法，是公正的。然而，遗传学和 蛋白质组学筛选不是我们的最终目标，但它们指导我们解释潜在的生物学机制。 概念和机制。重要的是，它们经常引导我们发现意想不到的和未探索的新事物。 开拓我们的视野。总之，我们使用一个全面的和跨学科的 方法，以打破新的基础，使变革性的发现，将提供新的 对基本生物过程的机械见解，特别是那些 受CRL监管。目前提出的研究将涵盖所有的机制研究 在我们的实验室进行，涉及上述区域i-iii。特别是，我们将利用 在泛素领域公认的专业知识，以发现分子机制， 控制信号传导途径、自噬、细胞周期进程和DNA修复。 此外，我们将进行生化，细胞和体内分析，以阐明CRL是如何 被调节为在不同的细胞命运之间起开关的作用。这些发现将大大 推进我们对关键细胞过程的正确执行的理解， 揭示了人类疾病的病因和治疗方法。