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.

所有动物，包括人类，都会经历 24 小时的活动周期，例如进食和睡眠。这种昼夜节律主要由外部线索（阳光）驱动，但由一组高度调节的生理和细胞过程维持。在细胞内部，选定的蛋白质会在 24 小时周期的特定时间点产生、变得活跃或失活。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 小时波动就会变得异常或消失。该研究项目研究了关键昼夜节律蛋白的调节和失活过程，以及这种形式的调节如何有助于维持昼夜节律。 许多蛋白质通过添加小分子（泛素）而失活，小分子作为针对这些蛋白质进行失活和处置的标志。添加泛素分子的蛋白质（称为 E3 连接酶）与其他蛋白质（称为 MAGE 蛋白质）配合完成泛素化过程。有 400 种 E3 连接酶和 60 种 MAGE 蛋白，细胞利用这两种蛋白的组合来准确识别要处理的目标蛋白以及何时进行此过程。我们之前由 NSERC 资助的研究表明，当 MAGEL2 蛋白缺失时（在基因工程小鼠中），昼夜节律会被扰乱。我们现在将重点发现 MAGEL2 如何与许多对昼夜节律很重要的 E3 连接酶蛋白相互作用。我们将测试 MAGEL2 是否影响 E3 连接酶将泛素添加到关键昼夜节律蛋白的能力，以及 MAGEL2 是否调节昼夜节律蛋白的稳定性和功能。该项目将揭示 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。