Impacting Cell Growth through altered circadian proteolysis

7.项目摘要/摘要 生物钟最近已经被认为是一系列广泛的 生理过程，包括葡萄糖稳态、血压调节和 癌症。此外，通过流行病学研究证实，昼夜节律 分裂会增加几种癌症的发病率。然而，分子基础是 这些现象还没有被很好地理解。这项提议的基本假设是 昼夜节律时钟成分蛋白Cry2通过促进一种 众所周知的致癌蛋白，原癌基因c-Myc，以及环境昼夜节律 由于倒班或慢性时差造成的干扰会改变Cry2的表达，从而增加癌症风险 导致c-Myc活性增加。推进我们对这些功能的理解 相互作用可能突出新的治疗和调控战略，以预防和/或 治疗疾病。我们之前的研究发现了生物钟成分隐花色素 (Cry1和Cry2)作为营养和DNA损伤反应转录调节因子 它们对AMPK和DNA磷酸化的敏感性 疱疹病毒相关泛素特异性蛋白水解酶损伤诱导的脱泛素 (Hausp，也就是USP7)。最近，我们有了一个意想不到的发现(如中所述 这里的初步数据)，Cry2是调节 通过靶向蛋白酶体破坏c-Myc的稳定性。在我们的过程中 研究，我们创造了独特的工具和专业知识，使我们能够使用生化， 用遗传学、分子和生理学的方法来揭示生物钟和 细胞生长和肿瘤发展中的昼夜节律蛋白Cry2，专门针对以下问题：1) 人类CRY2是否通过促进MYC家族的降解来保护细胞免于转化 蛋白质？2)抑制和蛋白质分解在生物中的相对重要性是什么？ Cry2？3)依赖于Cry2的Myc周转的中断是否参与了 肿瘤是由慢性时差或倒班工作引起的？

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?