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: 10226276
• 负责人: Katja A Lamia
• 金额: $ 44.26万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226276
• 关键词: 5' -AMP-activated protein kinase; ARNTL gene; Behavior; Biochemical Genetics; Biological; Biological Process; Blood Pressure; Breast Cancer Model; Cancer Etiology; Carcinogens; Cell Culture Techniques; Cell Proliferation; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Clock protein; Complex; DNA Damage; Data; Deubiquitination; Development; Disease; Disease Progression; Exhibits; Exposure to; Family member; Frequencies; Generations; Genetic; Genetic Transcription; Herpesviridae; Human; Incidence; Ionizing radiation; Jet Lag Syndrome; Lung; Lymphoma; MYC Family Protein; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Molecular; Mus; Mutate; Nutrient; Occupational Health; Oncogenic; Outcome; Output; Pathway interactions; Periodicity; Phosphorylation; Physiological; Physiological Processes; Physiology; Point Mutation; Post-Translational Regulation; Predisposition; Protein Isoforms; Proteins; Proteolysis; Proto-Oncogene Proteins c-myc; Public Health; Regulation; Relative Risks; Repression; Role; TP53 gene; The Cancer Genome Atlas; Therapeutic; Time; Transactivation; Transcription Repressor; Ubiquitination; United States; World Health Organization; blood glucose regulation; c-myc Genes; c-myc Proto-Oncogenes; cancer cell; cancer risk; cancer type; cell growth; cell transformation; circadian; circadian pacemaker; cryptochrome; epidemiology study; knowledge base; mammary; metaplastic cell transformation; mouse model; multicatalytic endopeptidase complex; mutant; novel; novel therapeutics; prevent; recruit; response; safety practice; shift work; small molecule; tool; transcription factor; tumor; tumorigenesis; ubiquitin-protein ligase; ubiquitin-specific protease

7. 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 a well-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?

7。项目摘要/摘要 昼夜节律钟最近被公认为是一系列广泛的调节器 生理过程，包括葡萄糖稳态，血压调节和 癌症。此外，通过流行病学研究，它是昼夜节律的良好确定的 破坏增加了几种类型的癌症的发生率。但是，分子基础 这些现象尚不清楚。该提议的基本假设是 昼夜节律成分蛋白CRY2通过促进破坏 众所周知的癌症引起蛋白质，原始癌基因C-MYC和环境昼夜节律 由于转移工作或慢性喷气滞后而导致的破坏通过改变CRY2表达来增强癌症的风险 导致C-MYC活性增加。推进我们对这些的功能理解 互动可能会突出预防和/或 治疗疾病。我们以前的研究确定了昼夜节律成分加密斑块 （Cry1和Cry2）作为营养和DNA损伤响应转录调节剂 它们通过AMP激活的蛋白激酶（AMPK）和DNA对磷酸化的敏感性 与疱疹病毒相关的泛素特异性蛋白酶的损伤引起的去泛素化 （Hausp，又名USP7）。最近，我们做出了意想不到的发现（描述了 这里的初步数据）Cry2是调节的复合物的必需物理成分 C-MYC的稳定性通过将其靶向蛋白酶体破坏。在我们的过程中 研究，我们生成了独特的工具和专业知识，使我们能够使用生化， 遗传，分子和生理方法揭示了昼夜节律的作用 昼夜节律蛋白Cry2在细胞生长和肿瘤发育中，专门针对：1） 人Cry2是否通过促进MYC家族的降解来保护细胞免受转化 蛋白质？ 2）抑制和蛋白水解在生物学中的相对重要性是什么 Cry2的功能？ 3）是涉及增加的CRY2依赖性MYC的破坏 由慢性喷射滞后或班次工作引起的肿瘤发生？