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Impacting Cell Growth through altered circadian proteolysis

通过改变昼夜蛋白水解影响细胞生长

基本信息

批准号：
9982673
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
项目类别：
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/9982673
关键词：
5&apos -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 Mammary gland 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 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

项目摘要

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. 项目总结/文摘