PLK1- AND BETA-TRCP-DEPENDENT DEGRADATION OF BORA CONTROLS MITOTIC PROGRESSION

BORA 的 PLK1 和 β-TRCP 依赖性降解控制有丝分裂进展

• 批准号: 7723686
• 负责人: GUOWEI FANG
• 金额: $ 0.08万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723686
• 关键词: Anaphase; Cell Cycle Progression; Cell Cycle Proteins; Computer Retrieval of Information on Scientific Projects Database; Funding; Grant; Institution; Kinetochores; Mediating; Metaphase; Microtubule Polymerization; Mitosis; Mitotic; Mutation; Phosphotransferases; Physiological; Proteins; Proteolysis; Proteomics; Regulation; Research; Research Personnel; Resources; Sister; Sister Chromatid; Source; United States National Institutes of Health; Variant; beta-Transducin Repeat-Containing Proteins; functional genomics; multicatalytic endopeptidase complex; segregation; ubiquitin ligase

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Through a convergence of functional genomic and proteomic studies, we identify Bora as a previously unknown cell cycle protein that interacts with the Plk1 kinase and the SCF-beta-TrCP ubiquitin ligase. We show that the Bora protein peaks in G2 and is degraded by proteasomes in mitosis. Proteolysis of Bora requires the Plk1 kinase activity and is mediated by SCF-beta-TrCP. Plk1 phosphorylates a conserved DSGxxT degron in Bora and promotes its interaction with beta-TrCP. Mutations in this degron stabilize Bora. Expression of a nondegradable Bora variant prolongs the metaphase and delays anaphase onset, indicating a physiological requirement of Bora degradation. Interestingly, the activity of Bora is also required for normal mitotic progression, as knockdown of Bora activates the spindle checkpoint and delays sister chromatid segregation. Mechanistically, Bora regulates spindle stability and microtubule polymerization and promotes tension across sister kinetochores during mitosis. We conclude that tight regulation of the Bora protein by its synthesis and degradation is critical for cell cycle progression.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 通过融合功能基因组学和蛋白质组学研究，我们确定Bora作为一个以前未知的细胞周期蛋白，与Plk 1激酶和SCF-β-TrCP泛素连接酶相互作用。我们发现，Bora蛋白在G2期达到峰值，并在有丝分裂中被蛋白酶体降解。Bora的蛋白水解需要Plk 1激酶活性，并由SCF-β-TrCP介导。Plk 1磷酸化Bora中保守的DSGxxT降解决定子并促进其与β-TrCP的相互作用。在这个降解决定子中的突变稳定了Bora。一个不可降解的宝来变异体的表达，使中期和后期开始延迟，表明宝来降解的生理要求。有趣的是，Bora的活性也是正常有丝分裂进程所必需的，因为Bora的敲低激活纺锤体检查点并延迟姐妹染色单体分离。在机械上，Bora调节纺锤体稳定性和微管聚合，并在有丝分裂期间促进姐妹动粒之间的张力。我们的结论是，严格监管的Bora蛋白的合成和降解是至关重要的细胞周期进程。