Exploration of a melanoma antigen (MAGE)-E3 ubiquitin ligase circuit governing circadian rhythm

探索黑色素瘤抗原 (MAGE)-E3 泛素连接酶控制昼夜节律的电路

• 批准号: RGPIN-2014-05777
• 负责人: Wevrick, Rachel
• 金额: $ 2.55万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=567380
• 关键词: Exploration; melanoma; antigen; MAGE; E3

All animals, including humans, undergo a 24-hour cycle of activities such as eating and sleeping. This circadian rhythm is primarily driven by external cues (sunlight) but is maintained by a highly regulated set of physiological and cellular processes. Inside the cell, selected proteins are produced, become active, or are inactivated at specific time points in the 24-hour cycle. These proteins are required for circadian rhythm: without them, the 24-hour oscillation of sleeping and other behaviours becomes abnormal or absent. This research program investigates the process by which key circadian rhythm proteins are regulated and inactivated, and how this form of regulation contributes to the maintenance of circadian rhythm. Many proteins are inactivated through the addition of a small molecule (ubiquitin), which serves as a flag that targets these proteins for inactivation and disposal. The proteins that add the ubiquitin molecule (called E3 ligases) cooperate with other proteins (called MAGE proteins) to complete the ubiquitylation process. There are 400 E3 ligases and 60 MAGE proteins, and combinations of these two types of proteins are used by the cell to accurately recognize which proteins to target for disposal and when to go about this process. Our previous NSERC-funded research demonstrated that when the MAGEL2 protein is absent (in a genetically engineered mouse), circadian rhythm is disrupted. We will now focus on discovering how MAGEL2 interacts with the many E3 ligase proteins that are important in circadian rhythm. We will test whether MAGEL2 affects the ability of the E3 ligases to add ubiquitin to key circadian rhythm proteins, and whether MAGEL2 regulates the stability and function of circadian rhythm proteins. This program will shed light on the molecular basis of the 24-hour circadian rhythm that is one of the most fundamental properties of animal behavior.

包括人类在内的所有动物都经历了24小时的活动，例如饮食和睡眠。这种昼夜节律主要是由外部提示（阳光）驱动的，但由一组高度调节的生理和细胞过程驱动。在细胞内部，在24小时循环的特定时间点上产生，活跃或在特定时间点失活。这些蛋白质是昼夜节律所必需的：没有它们，睡眠和其他行为的24小时振荡就会变得异常或不存在。该研究计划研究了关键的昼夜节律蛋白被调节和灭活的过程，以及这种调节形式如何促进昼夜节律的维持。 通过添加小分子（泛素），许多蛋白质被灭活，该蛋白用作靶向这些蛋白质以灭活和处置的标志。添加泛素分子（称为E3连接酶）的蛋白质与其他蛋白质（称为MAGE蛋白）合作以完成泛素化过程。有400个E3连接酶和60个MAGE蛋白，细胞使用这两种类型的蛋白质的组合来准确识别要靶向的处置以及何时进行此过程的蛋白质。我们以前由NSERC资助的研究表明，当不存在MAGEL2蛋白（在基因工程小鼠中）时，昼夜节律会破坏。现在，我们将专注于发现Magel2如何与昼夜节律重要的许多E3连接酶蛋白相互作用。我们将测试MAGEL2是否影响E3连接酶在关键的昼夜节律蛋白中添加泛素的能力，以及Magel2是否调节昼夜节律节奏蛋白的稳定性和功能。该程序将阐明24小时昼夜节律的分子基础，这是动物行为最基本的特性之一。