Impacting Cell Growth through altered circadian proteolysis

项目摘要/摘要 生物钟最近已被认为是一系列生理活动的调节器 这些过程包括葡萄糖稳态、血压调节和癌症。另外，它是很好的 通过流行病学研究证实，昼夜节律紊乱会增加几种 癌症的类型。然而，这些现象的分子基础还没有被很好地理解。这个 这一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的破坏来增加癌症风险，原癌基因c- MYC，以及由于倒班或慢性时差造成的环境昼夜节律紊乱会增加癌症的风险 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出新的治疗和调节策略 预防和/或治疗疾病。我们之前的研究确定了昼夜节律时钟成分 作为营养和DNA损伤反应转录调节因子的隐色素(Cry1和Cry2) 它们对AMP活化蛋白激酶(AMPK)和DNA磷酸化的敏感性 疱疹病毒相关泛素特异蛋白酶(Hausp，又名：HAUSP)的损伤诱导去泛素化 USP7)。最近，我们有了一个意想不到的发现(在这里的初步数据中描述)，Cry2 是复合体的必需物理成分，通过靶向c-Myc来调节c-Myc的稳定性 蛋白酶体的破坏。在我们的研究过程中，我们产生了独特的工具和 使我们能够使用生化、遗传、分子和生理方法的专业知识 揭示生物钟和昼夜节律蛋白Cry2在细胞生长和肿瘤中的作用 开发，专门针对问：1)人类CRY2是否通过以下方式保护细胞免受转化 促进MYC家族蛋白的降解？2)抑制和抑制的相对重要性是什么？ Cry2？生物学功能中的蛋白分解？3)是依赖于Cry2的Myc周转中断 是否与慢性时差或倒班工作导致的肿瘤发生增加有关？

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?