Impacting Cell Growth through altered circadian proteolysis

7.项目概要/摘要 昼夜节律钟最近已被认为是多种生物钟的调节剂。 生理过程，包括葡萄糖稳态，血压调节，和 癌此外，通过流行病学研究已经很好地建立了昼夜节律， 破坏会增加几种癌症的发病率。然而， 这些现象还没有得到很好的理解。这一建议的基本假设是， 生物钟组成蛋白Cry2通过促进细胞凋亡来调节癌症风险。 一种著名的致癌蛋白，原癌基因c-Myc，以及环境昼夜节律， 轮班工作或慢性时差引起的中断通过改变Cry2表达增加癌症风险 导致c-Myc活性增加。推进我们对这些功能的理解 相互作用可能突出了新的治疗和调节策略，用于预防和/或 治疗疾病我们以前的研究确定了生物钟成分隐花色素 (Cry1和Cry2）作为营养和DNA损伤响应性转录调节因子， 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性蛋白酶损伤诱导的去泛素化 （Hausp，a.k.a. USP 7）。最近，我们有了一个意想不到的发现（见 这里的初步数据），Cry2是一个复杂的调节所需的物理成分， 通过蛋白酶体靶向破坏c-Myc的稳定性。在我们的 研究，我们已经产生了独特的工具和专业知识，使我们能够使用生物化学， 遗传、分子和生理学方法，以揭示生物钟和 昼夜节律蛋白Cry2在细胞生长和肿瘤发展中的作用，具体目的是问：1） 人β 2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)阻遏和蛋白水解在生物学中的相对重要性是什么？ Cry2？和3）Cry2依赖性Myc周转的破坏是否涉及增加的 慢性时差或轮班工作引起的肿瘤？

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?