Impacting Cell Growth through altered circadian proteolysis

项目总结/摘要 生物钟最近已被认为是多种生理调节剂， 过程，包括葡萄糖稳态，血压调节和癌症。此外， 通过流行病学研究确定，昼夜节律紊乱会增加几种疾病的发病率， 癌症的类型。然而，这些现象的分子基础还没有得到很好的理解。的 这一提议的基本假设是，生物钟组分蛋白Cry 2调节 癌症风险通过促进一种众所周知的致癌蛋白质，原癌基因c- 由于轮班工作或慢性时差引起的环境昼夜节律紊乱会增强癌症 通过改变Cry 2表达导致c-Myc活性增加来降低风险。推进我们的职能 了解这些相互作用可能会突出新的治疗和调节策略， 预防和/或治疗疾病。我们以前的研究确定了生物钟的组成部分 隐花色素（Cry 1和Cry 2）作为营养和DNA损伤响应性转录调节因子， 由于它们对AMP活化蛋白激酶（AMPK）和DNA磷酸化的敏感性， 疱疹病毒相关的泛素特异性蛋白酶（Hausp，a.k.a. USP 7）。最近，我们有了一个意外的发现（在这里的初步数据中描述）， 是一种复合物所需的物理成分，该复合物通过靶向c-Myc来调节其稳定性， 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， 专业知识，使我们能够使用生物化学，遗传学，分子和生理学方法， 揭示生物钟和生物钟蛋白Cry 2在细胞生长和肿瘤中的作用 开发，特别是旨在问：1）人类p53 2是否通过以下途径保护细胞免于转化： 促进MYC家族蛋白的降解？2)什么是镇压的相对重要性， 蛋白水解的生物学功能的Cry 2？和3）是Cry 2依赖性Myc周转的破坏 与慢性时差或轮班工作引起的肿瘤发生增加有关吗？

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?