Impacting Cell Growth through altered circadian proteolysis

通过改变昼夜蛋白水解影响细胞生长

• 批准号: 10367294
• 负责人: Katja A Lamia
• 金额: $ 0.29万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10367294
• 关键词: 5' -AMP-activated protein kinase; Biochemical Genetics; Biological Process; Blood Pressure; Cancer Etiology; Chronic; Circadian Dysregulation; Complex; DNA Damage; Data; Deubiquitination; Development; Disease; Genetic Transcription; Herpesviridae; Human; Incidence; Jet Lag Syndrome; MYC Family Protein; Malignant Neoplasms; Molecular; Nutrient; Occupational Health; Phosphorylation; Physiological; Physiological Processes; Predisposition; Proteins; Proteolysis; Public Health; Repression; Role; United States; blood glucose regulation; c-myc Genes; c-myc Proto-Oncogenes; cancer risk; cancer type; cell growth; cell transformation; circadian; circadian pacemaker; cryptochrome; epidemiology study; knowledge base; multicatalytic endopeptidase complex; novel; novel therapeutics; prevent; safety practice; shift work; tool; tumor; tumorigenesis; ubiquitin-specific protease

Project Summary/Abstract Circadian clocks have recently become recognized as modulators of a wide array of physiological processes, including glucose homeostasis, blood pressure modulation, and cancer. In addition, it is well established through epidemiological studies that circadian disruption increases the incidence of several types of cancer. However, the molecular basis for these phenomena is not well understood. The underlying hypothesis of this proposal is that the circadian clock component protein Cry2 modulates cancer risk by promoting the destruction of awell-known cancer causing protein, the proto-oncogene c- Myc, and that environmental circadian disruption due to shift work or chronic jet lag enhances cancer risk by altering Cry2 expression leading to increased c-Myc activity. Advancing our functional understanding of these interactions may highlight new therapeutic and regulatory strategies for preventing and/or treating disease. Our previous studies identified the circadian clock component cryptochromes (Cry1 and Cry2) as nutrient and DNA damage responsive transcriptional regulators by virtue of their susceptibility to phosphorylation by AMP-activated protein kinase (AMPK) and DNA damage-induced deubiquitination by Herpes virus associated ubiquitin specific protease (Hausp, a.k.a. Usp7). Most recently, we made the unexpected discovery (described in preliminary data here) that Cry2 is a required physical component of a complex that regulates the stability of c-Myc by targeting it for destruction by the proteasome. In the course of our studies, we have generated unique tools and expertise that enable us to use biochemical, genetic, molecular and physiological approaches to uncover the roles of circadian clocks and of the circadian protein Cry2 in cell growth and tumor development, specifically aimed at asking: 1) Does human CRY2 protect cells from transformation by promoting degradation of MYC family proteins? 2) What is the relative importance of repression and proteolysis in the biological functions of Cry2? and 3) Is disruption of Cry2-dependent Myc turnover involved in increased tumorigenesis caused by chronic jet lag or shift work?

项目概要/摘要 生物钟最近被认为是多种生理的调节器 过程，包括葡萄糖稳态、血压调节和癌症。另外，还好 流行病学研究表明，昼夜节律紊乱会增加多种疾病的发病率 癌症的类型。然而，这些现象的分子基础尚不清楚。这 该提议的基本假设是生物钟成分蛋白 Cry2 调节 通过促进一种众所周知的致癌蛋白质——原癌基因 c 的破坏来降低癌症风险—— Myc，轮班工作或慢性时差导致的环境昼夜节律紊乱会加剧癌症 改变 Cry2 表达导致 c-Myc 活性增加的风险。推进我们的功能 对这些相互作用的理解可能会突显新的治疗和监管策略 预防和/或治疗疾病。我们之前的研究确定了生物钟的组成部分 隐花色素（Cry1 和 Cry2）作为营养和 DNA 损伤响应性转录调节因子 由于它们对 AMP 激活蛋白激酶 (AMPK) 和 DNA 磷酸化的敏感性 疱疹病毒相关泛素特异性蛋白酶（Hausp，又名：损伤诱导的去泛素化） 美国药典7)。最近，我们意外地发现（在此处的初步数据中进行了描述）Cry2 是复合物的必需物理成分，通过靶向 c-Myc 来调节 c-Myc 的稳定性 被蛋白酶体破坏。在我们的研究过程中，我们创造了独特的工具和 专业知识使我们能够利用生化、遗传、分子和生理学方法来 揭示生物钟和生物钟蛋白 Cry2 在细胞生长和肿瘤中的作用 开发，特别旨在询问：1）人类 CRY2 是否通过以下方式保护细胞免于转化： 促进 MYC 家族蛋白的降解？ 2）镇压和镇压的相对重要性是什么？ Cry2蛋白水解的生物学功能？ 3) Cry2 依赖性 Myc 周转是否受到干扰 是否与慢性时差或轮班工作导致肿瘤发生增加有关？