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/Cyclin复合物通过真核细胞周期驱动进程。 进入有丝分裂由Cdk 1（Cdc 2）/Cyclin B复合物触发，而M 期退出需要细胞周期蛋白B降解和有丝分裂相的去磷酸化。 磷蛋白细胞周期蛋白B在M期退出时的破坏是由 APC（后期促进复合物），一种多蛋白E3泛素连接酶， 泛素化细胞周期蛋白B并促进其蛋白酶体降解。多重因素 合作防止过早激活，并确保及时灭活 装甲运兵车在脊椎动物卵中，其在M期被长时间阻滞， 此时，APC受到称为细胞生长抑制因子（CSF）的活性的抑制。 最近在非洲爪蟾和小鼠卵中的发现强烈暗示了p53 2 蛋白质作为CSF活性的关键组分，负责直接抑制 APC。我们并不确切地了解BMP 2如何影响APC抑制， 尽管我们最近发现， 比化学计量学上的要多。此外，我们的数据表明， Cdc 2的功能至少部分地通过Cdc 2介导的 磷酸化，虽然磷酸酶复合物的性质， 这是未知的。这项建议的目的是 阐明APC抑制的机制，并确定如何 CSF调节β 2。这种理解是至关重要的， 在减数分裂退出时APC激活可导致染色体分离错误， 严重的发育异常导致一系列先天缺陷。