Regulation of M phase exit

M相退出调节

• 批准号: 7933641
• 负责人: Sally A Kornbluth
• 金额: $ 30.39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933641
• 关键词: Aneuploidy; Cell Cycle; Characteristics; Chromosome Segregation; Chromosomes; Complex; Congenital Abnormality; Cyclin B; Cyclins; DNA Sequence Rearrangement; Data; Defect; Development; Ensure; Eukaryotic Cell; Germ Cells; Goals; Lead; Link; MOS pp39 Serine/Threonine Kinase; Mediating; Meiosis; Mitosis; Mitotic; Mitotic spindle; Molecular; Mus; Nature; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Protein Dephosphorylation; Protein Inhibition; Proteins; Regulation; Role; Signal Pathway; Somatic Cell; Time; Xenopus; anaphase-promoting complex; carcinogenesis; egg; novel; operation; premature; prevent; ubiquitin-protein ligase

Cdk/Cyclin complexes drive progression through the eukaryotic cell cycle. Entry into mitosis is triggered by Cdk1 (Cdc2)/Cyclin B complexes, while M phase exit requires Cyclin B degradation and dephosphorylation of mitotic phosphoproteins. The destruction of Cyclin B at M phase exit is driven by the APC (anaphase promoting complex), a multi-protein E3 ubiquitin ligase, which ubiquitylates Cyclin B and promotes its proteasomal degradation. Multiple factors cooperate to prevent premature activation and ensure timely inactivation of the APC. In vertebrate eggs, which are arrested in M phase for prolonged periods of time, the APC is restrained by an activity known as Cytostatic Factor (CSF). Recent findings in both Xenopus and mouse eggs have strongly implicated Emi2 protein as a critical component of CSF activity, responsible for direct inhibition of the APC. We do not understand precisely how Emi2 effects APC inhibition, though we have recently found that Emi2 appears to act catalytically, rather than stoichiometrically, as is generally believed. Moreover, our data indicate that Emi2 function is inhibited, at least in part, through direct Cdc2-mediated phosphorylation, though the nature of the phosphatase complexes that counter this to activate Emi2 function are unknown. The aims of this proposal are to elucidate the mechanism(s) of APC inhibition by Emi2 and to determine how Emi2 is regulated by CSF. This understanding is critical in that inappropriate APC activation at meiotic exit can lead to errors in chromosome segregation and severe developmental abnormalities underlying a range of birth defects.

CDK/细胞周期蛋白复合物可以通过真核细胞周期驱动进展。 进入有丝分裂是由CDK1（CDC2）/细胞周期蛋白B复合物触发的，而M 相位出口需要细胞周期蛋白B降解和脱磷酸化丝分裂。 磷蛋白。 M相出口处的细胞周期蛋白B的破坏是由 APC（后期促进复合物），一种多蛋白E3泛素连接酶，它 泛素化细胞周期蛋白B并促进其蛋白酶体降解。多种因素 合作以防止过早激活并确保及时失活 APC。在脊椎动物卵中，该卵在M期被捕长时间 时间，APC受到称为细胞抑制因子（CSF）的活性的约束。 爪蟾和小鼠卵的最新发现强烈暗示EMI2 蛋白质是CSF活性的关键成分，负责直接抑制 APC。我们不确定EMI2如何影响APC的抑制作用， 尽管我们最近发现EMI2似乎是催化作用的，而是 通常认为，比石化。此外，我们的数据表明 EMI2函数至少部分通过直接CDC2介导的抑制 磷酸化，尽管磷酸酶复合物的性质 激活EMI2函数是未知的。该提议的目的是 阐明EMI2抑制APC的机制，并确定如何 EMI2由CSF调节。这种理解至关重要 减数分裂出口处的APC激活会导致染色体隔离错误和 一系列先天缺陷的严重发育异常。