Madgwick Suzanne, Jones Keith T
Institute for Cell and Molecular Biosciences, The Medical School, University of Newcastle, Newcastle NE2 4HH, England, UK.
Cell Div. 2007 Jan 26;2:4. doi: 10.1186/1747-1028-2-4.
Oocytes from higher chordates, including man and nearly all mammals, arrest at metaphase of the second meiotic division before fertilization. This arrest is due to an activity that has been termed 'Cytostatic Factor'. Cytostatic Factor maintains arrest through preventing loss in Maturation-Promoting Factor (MPF; CDK1/cyclin B). Physiologically, Cytostatic Factor - induced metaphase arrest is only broken by a Ca2+ rise initiated by the fertilizing sperm and results in degradation of cyclin B, the regulatory subunit of MPF through the Anaphase-Promoting Complex/Cyclosome (APC/C). Arrest at metaphase II may therefore be viewed as being maintained by inhibition of the APC/C, and Cytostatic Factor as being one or more pathways, one of which inhibits the APC/C, consorting in the preservation of MPF activity. Many studies over several years have implicated the c-Mos/MEK/MAPK pathway in the metaphase arrest of the two most widely studied vertebrates, frog and mouse. Murine downstream components of this cascade are not known but in frog involve members of the spindle assembly checkpoint, which act to inhibit the APC/C. Interesting these downstream components appear not to be involved in the arrest of mouse eggs, suggesting a lack of conservation with respect to c-Mos targets. However, the recent discovery of Emi2 as an egg specific APC/C inhibitor whose degradation is Ca2+ dependent has greatly increased our understanding of MetII arrest. Emi2 is involved in both the establishment and maintenance of metaphase II arrest in frog and mouse suggesting a conservation of metaphase II arrest. Its identity as the physiologically relevant APC/C inhibitor involved in Cytostatic Factor arrest prompted us to re-evaluate the role of the c-Mos pathway in metaphase II arrest. This review presents a model of Cytostatic Factor arrest, which is primarily induced by Emi2 mediated APC/C inhibition but which also requires the c-Mos pathway to set MPF levels within physiological limits, not too high to induce an arrest that cannot be broken, or too low to induce parthenogenesis.
包括人类和几乎所有哺乳动物在内的高等脊索动物的卵母细胞在受精前停滞于第二次减数分裂中期。这种停滞是由于一种被称为“细胞静止因子”的活性物质。细胞静止因子通过防止成熟促进因子（MPF；CDK1/细胞周期蛋白B）的丧失来维持停滞状态。在生理上，细胞静止因子诱导的中期停滞仅通过受精精子引发的Ca2+升高来打破，并导致细胞周期蛋白B的降解，细胞周期蛋白B是MPF的调节亚基，通过后期促进复合物/细胞周期体（APC/C）实现降解。因此，中期II停滞可被视为通过抑制APC/C来维持，而细胞静止因子则是一种或多种途径，其中之一抑制APC/C，共同维持MPF活性。多年来的许多研究表明，c-Mos/MEK/MAPK途径与两种研究最广泛的脊椎动物——青蛙和小鼠的中期停滞有关。该级联反应在小鼠中的下游成分尚不清楚，但在青蛙中涉及纺锤体组装检查点的成员，其作用是抑制APC/C。有趣的是，这些下游成分似乎不参与小鼠卵子的停滞，这表明在c-Mos靶点方面缺乏保守性。然而，最近发现Emi2是一种卵子特异性的APC/C抑制剂，其降解依赖于Ca2+，这极大地增进了我们对中期II停滞的理解。Emi2参与青蛙和小鼠中期II停滞的建立和维持，这表明中期II停滞具有保守性。其作为参与细胞静止因子停滞的生理相关APC/C抑制剂的身份促使我们重新评估c-Mos途径在中期II停滞中的作用。本综述提出了一种细胞静止因子停滞的模型，该模型主要由Emi2介导的APC/C抑制诱导，但也需要c-Mos途径将MPF水平设定在生理限度内，既不能过高以至于诱导无法打破的停滞，也不能过低以至于诱导孤雌生殖。
