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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 通过功能基因组和蛋白质组学研究的收敛，我们将BORA鉴定为先前未知的细胞周期蛋白，与PLK1激酶和SCF-BETA-TRCP泛素连接酶相互作用。我们表明，bora蛋白在G2中峰，并在有丝分裂中被蛋白酶体降解。 BORA的蛋白水解需要PLK1激酶活性，并由SCF-BETA-TRCP介导。 PLK1磷酸化Bora中的保守的DSGXXT DEGRON，并促进其与β-TRCP的相互作用。此Degron中的突变稳定了Bora。不良的bora变体的表达延长了中期并延迟了后期的开始，表明生理上的bora降解需求。有趣的是，正常有丝分裂进展也需要BORA的活性，因为敲低BORA激活了主轴检查点并延迟了姐妹染色单体隔离。从机械上讲，Bora调节纺锤体稳定性和微管聚合，并在有丝分裂过程中促进姊妹动物学的张力。我们得出的结论是，通过其合成和降解对Bora蛋白的严格调节对于细胞周期进程至关重要。