INT6 and Moe1 interact with Cdc48 to regulate proteolyis

INT6 和 Moe1 与 Cdc48 相互作用来调节蛋白水解

• 批准号: 7284826
• 负责人: Joel H Otero
• 金额: $ 3.12万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284826
• 关键词: ATP phosphohydrolase; Agreement; Animal Model; Binding; Breast; Cells; Centrifugation; Chromosome Segregation; Chromosomes; Co-Immunoprecipitations; Complex; Data; EIF3S6 gene; Endoplasmic Reticulum; Family; Fellowship; Fission Yeast; Genes; Genetic; Goals; Homologous Gene; Individual; Lead; Length; Life; Link; Localized; Lung Neoplasms; Mediating; Microscopy; Mitosis; Mitotic; Mitotic spindle; Modeling; Names; Nuclear; Pharmaceutical Preparations; Process; Proteasome Binding; Protein Binding; Proteins; Proteolysis; Regulation; Role; Signaling Protein; Sucrose; Testing; Yeasts; base; cancer prevention; cancer type; gene function; in vivo; iodonitrotetrazolium; loss of function; multicatalytic endopeptidase complex; mutant; protein degradation; protein misfolding; receptor; tumor; tumorigenesis; yeast two hybrid system

DESCRIPTION (provided by applicant): Studies of the INT genes have led to the discovery of families of very important signaling proteins, and contributed significantly to the understanding of tumorigenesis. Among the INT genes, the function of INT6 is the least understood. Our lab has studied INT6 by using its homolog yin6 in the model organism Schizosaccharomyces pombe. Yin6 regulates mitotic progression (chromosome segregation and spindle dynamics) by positively regulating the assembly/localization of the proteasome. My overall goal is to further understand how Yin6 regulates proteolysis and mitosis. My study centers on another conserved protein, Moe1, to which Yin6 binds directly. Intriguingly, while Yin6 binds the proteasome, Moe1 does not, and our preliminary data show that Moe1 can interact with proteins that act as substrate receptors for the proteasome, such as Cdc48, which is an AAA ATPase, a key component in a process called ERAD (Endoplasmic Reticulum Associated Degradation), as well as in mitosis and spindle dynamics. This project will test the hypothesis that the Yin6-Moe1 links substrate selection, via Meet's binding to Cdc48, and proteolysis, via Yin6's binding to the proteasome, to facilitate protein degradation. Furthermore, I will test how this mechanism is involved in the regulation of ERAD and/or mitotic spindle disassembly. Thus, in Aim 1, further physical interactions in S. pombe will be studied to prove the formation of the complex in vivo. In Aim 2, the role of these interactions in regulating ERAD will be studied biochemically and genetically. Lastly, in Aim3, a role for the interaction of the Yin6-Moe1 complex with Cdc48 in regulating the formation of the mitotic spindle will be examined. The results of these studies are intended to provide a better understanding of how Int6, Moe1 and Cdc48 may be involved in tumorigenesis.

描述(由申请人提供)：对INT基因的研究导致了非常重要的信号蛋白家族的发现，并对理解肿瘤的发生做出了重要贡献。在INT基因中，INT6的功能了解最少。本实验室利用其同源基因Yin6在模式生物裂殖酵母中对INT6进行了研究。银六号通过正向调节蛋白酶体的组装/定位来调节有丝分裂进程(染色体分离和纺锤体动力学)。我的总体目标是进一步了解银六号是如何调控蛋白质分解和有丝分裂的。我的研究集中在另一种保守的蛋白质Moe1上，它直接与Yin6结合。有趣的是，虽然Yin6与蛋白酶体结合，但Moe1不结合，我们的初步数据表明，Moe1可以与作为蛋白酶体底物受体的蛋白质相互作用，例如CDC48，它是一种AAA ATPase，是称为ERAD(内质网相关降解)过程的关键成分，以及有丝分裂和纺锤体动力学。本项目将检验这样的假设，即银6-Moe1通过Met与CDC48结合进行底物选择，并通过银6‘S与蛋白酶体结合进行蛋白质降解，以促进蛋白质降解。此外，我将测试这一机制如何参与ERAD和/或有丝分裂纺锤体拆解的调节。因此，在目标1中，将研究S.pombe中的进一步物理相互作用，以证明该复合体在体内的形成。在目标2中，将从生物化学和遗传学角度研究这些相互作用在调节ERAD中的作用。最后，在Aim3中，将研究Yin6-Moe1复合体与CDC48相互作用在调节有丝分裂纺锤体形成中的作用。这些研究的结果旨在更好地了解Int6、Moe1和CDC48可能如何参与肿瘤的发生。