Biological functions of melanoma antigen (MAGE) proteins
黑色素瘤抗原 (MAGE) 蛋白的生物学功能
基本信息
- 批准号:RGPIN-2020-04961
- 负责人:
- 金额:$ 2.33万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2021
- 资助国家:加拿大
- 起止时间:2021-01-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The abundance and subcellular localization of proteins contributes to the ctivities that take place inside cells. Both protein stability and localization are determined in part by post-translational modification. The proposed research specifically considers the role of the reversible attachment of a 76 residue ubiquitin protein to substrate proteins, which dynamically changes the stability, activity, or subcellular localization of the ubiquitinated protein. For example, cell cycle proteins undergo highly regulated ubiquitination and deubiquitination, fine tuning their stability, activity and localization. However, the proteins that perform the reversible ubiquitination / deubiquitination processes, and other proteins that modify the activity of these ubiquitin ligases and deubiquitinases are poorly understood. Our previous research has demonstrated that Melanoma Antigen Gene (MAGE) proteins regulate the ubiquitination and deubiquitination of proteins important for a variety of physiological processes. In particular, the L2 member of the MAGE family of proteins (MAGEL2) regulates the intracellular localization and stability of other proteins. Our team found that MAGEL2 forms a functional complex with E3 ubiquitin ligases (e.g. RBX1-SCF) and deubiquitinases (e.g. USP7), thereby regulating circadian rhythm processes through effects on the activity and stability of master clock components. We found that MAGEL2 regulates the stability of BBS proteins important for the function of centrosomes and of cilia, subcellular organelles that sense and respond to signals in the extracellular environment. We found that MAGEL2 and another MAGE protein, namely necdin, regulate the intracellular shuttling of the leptin receptor through processes dependent on ESCRT (endosomal sorting complexes required for transport) machinery. Our research program objective is to explore the mechanisms for regulation of intracellular shuttling and stability of proteins by protein ubiquitination. The importance of MAGE proteins in this process is evident from the observations that mutation in the genes encoding MAGE proteins cause disease in humans (MAGEL2 in Schaaf-Yang syndrome, MAGED2 in antenatal Bartter syndrome, MAGEG1 in a chromosome breakage syndrome), with phenotypes in mouse MAGE gene knockouts as well. We will use molecular and cellular models to determine the role of MAGE proteins, which are components of ubiquitination (Ub) complexes. Specifically, we will use protein-protein interaction techniques to identify components of the MAGE-ubiquitin ligase-deubiquitinase complexes; determine how MAGE proteins fine tune cellular processes using cell lines in culture and 3) examine how genes and proteins important in cellular processes are regulated by ubiquitination in tissues. Ultimately, this research will explore how modification of proteins by ubiquitination and deubiquitination fine tunes the activity of proteins in the cell.
蛋白质的丰度和亚细胞定位有助于在细胞内部发生的ctivition。蛋白质稳定性和定位均部分通过翻译后修饰确定。提出的研究专门考虑了76个残基泛素蛋白在底物蛋白上的可逆附着的作用,该蛋白会动态地改变泛素化蛋白的稳定性,活性或亚细胞定位。例如,细胞周期蛋白经历高度调节的泛素化和去泛素化,微调其稳定性,活性和定位。然而,对这些泛素连接酶和去泛素酶的活性的其他蛋白质进行了可逆的泛素化 /去泛素化过程。我们先前的研究表明,黑色素瘤抗原基因(MAGE)蛋白调节对各种生理过程重要的蛋白质的泛素化和去泛素化。特别是,蛋白质法师家族的L2成员(MAGEL2)调节了其他蛋白质的细胞内定位和稳定性。我们的团队发现MAGEL2与E3泛素连接酶(例如RBX1-SCF)和去泛素酶(例如USP7)形成功能复合物,从而通过对主时钟成分的活性和稳定性的影响来调节昼夜节律过程。我们发现MAGEL2调节BBS蛋白对中心体和纤毛,纤毛的功能重要的稳定性,在细胞外环境中感知并响应信号的亚细胞细胞器。我们发现MAGEL2和另一种法师蛋白,即NECDIN,通过取决于ESCRT(运输所需的内体分类复合物)机械的过程来调节瘦素受体的细胞内穿梭。我们的研究计划目标是探索通过蛋白质泛素化调节蛋白质内穿梭和稳定性的机制。从这一过程中,法师蛋白在此过程中的重要性可以明显看出,编码法师蛋白的基因突变引起人类疾病(Magel2 schaaf-Yang综合征,MAGED2,MAGED2,MAGED2,产前Bartter综合征中的Maged2,Mageg1,Mageg1,Mageg1,Mageg1中的Mageg1中的Mageg1中的Mageg1中的Mageg1中的染色体破裂综合症中的现象中的现象中均为小鼠Mage Mage Mage Mage Mage Mage Mage Mage Mage and and and and and and and。我们将使用分子和细胞模型来确定MAGE蛋白的作用,后者是泛素化(UB)复合物的组成部分。具体而言,我们将使用蛋白质 - 蛋白质相互作用技术来识别法师 - 泛素连接酶 - 非素酶复合物的成分。确定法术蛋白如何使用培养物中细胞系进行微调细胞过程,3)研究如何通过组织中的泛素化来调节细胞过程中重要的基因和蛋白质。最终,这项研究将探讨如何通过泛素化和去泛素化修饰蛋白质如何调节细胞中蛋白质的活性。
项目成果
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科研奖励数量(0)
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Wevrick, Rachel其他文献
Clinical and genetic analysis of children with a dual diagnosis of Tourette syndrome and autism spectrum disorder
- DOI:
10.1016/j.jpsychires.2019.01.023 - 发表时间:
2019-04-01 - 期刊:
- 影响因子:4.8
- 作者:
Carias, Karin Vanessa;Wevrick, Rachel - 通讯作者:
Wevrick, Rachel
Hypothalamic AAV-BDNF gene therapy improves metabolic function and behavior in the Magel2-null mouse model of Prader-Willi syndrome.
- DOI:
10.1016/j.omtm.2022.09.012 - 发表时间:
2022-12-08 - 期刊:
- 影响因子:0
- 作者:
Queen, Nicholas J.;Zou, Xunchang;Anderson, Jacqueline M.;Huang, Wei;Appana, Bhavya;Komatineni, Suraj;Wevrick, Rachel;Cao, Lei - 通讯作者:
Cao, Lei
Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development
- DOI:
10.1093/hmg/ddn344 - 发表时间:
2009-01-15 - 期刊:
- 影响因子:3.5
- 作者:
Miller, Nichol L. G.;Wevrick, Rachel;Mellon, Pamela L. - 通讯作者:
Mellon, Pamela L.
Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome
- DOI:
10.1093/hmg/ddm225 - 发表时间:
2007-11-15 - 期刊:
- 影响因子:3.5
- 作者:
Bischof, Jocelyn M.;Stewart, Colin L.;Wevrick, Rachel - 通讯作者:
Wevrick, Rachel
Preclinical Testing in Translational Animal Models of Prader-Willi Syndrome: Overview and Gap Analysis
- DOI:
10.1016/j.omtm.2019.03.001 - 发表时间:
2019-06-14 - 期刊:
- 影响因子:4.7
- 作者:
Carias, K. Vanessa;Wevrick, Rachel - 通讯作者:
Wevrick, Rachel
Wevrick, Rachel的其他文献
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{{ truncateString('Wevrick, Rachel', 18)}}的其他基金
Biological functions of melanoma antigen (MAGE) proteins
黑色素瘤抗原 (MAGE) 蛋白的生物学功能
- 批准号:
RGPIN-2020-04961 - 财政年份:2020
- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
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 - 财政年份:2018
- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
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 - 财政年份:2017
- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
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 - 财政年份:2016
- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
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 - 财政年份:2015
- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
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 - 财政年份:2014
- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
Function of magel2 in circadian rhythm
Magel2 在昼夜节律中的功能
- 批准号:
227147-2008 - 财政年份:2012
- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
Function of magel2 in circadian rhythm
Magel2 在昼夜节律中的功能
- 批准号:
227147-2008 - 财政年份:2011
- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
Function of magel2 in circadian rhythm
Magel2 在昼夜节律中的功能
- 批准号:
227147-2008 - 财政年份:2010
- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
Function of magel2 in circadian rhythm
Magel2 在昼夜节律中的功能
- 批准号:
227147-2008 - 财政年份:2009
- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual
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Biological functions of melanoma antigen (MAGE) proteins
黑色素瘤抗原 (MAGE) 蛋白的生物学功能
- 批准号:
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- 资助金额:
$ 2.33万 - 项目类别:
Discovery Grants Program - Individual