Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Rumburska 89, Libechov CZ-27721, Czech Republic.
Mol Hum Reprod. 2010 Sep;16(9):654-64. doi: 10.1093/molehr/gaq034. Epub 2010 May 7.
Mammalian oocytes are arrested at prophase I until puberty when luteinizing hormone (LH) induces resumption of meiosis of follicle-enclosed oocytes. Resumption of meiosis is tightly coupled with regulating cyclin-dependent kinase 1 (CDK1) activity. Prophase I arrest depends on inhibitory phosphorylation of CDK1 and anaphase-promoting complex-(APC-CDH1)-mediated regulation of cyclin B levels. Prophase I arrest is maintained by endogenously produced cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA) that in turn phosphorylates (and activates) the nuclear kinase WEE2. In addition, PKA-mediated phosphorylation of the phosphatase CDC25B results in its cytoplasmic retention. The combined effect maintains low levels of CDK1 activity that are not sufficient to initiate resumption of meiosis. LH triggers synthesis of epidermal growth factor-like factors in mural granulosa cells and leads to reduced cGMP transfer from cumulus cells to oocytes via gap junctions that couple the two cell types. cGMP inhibits oocyte phosphodiesterase 3A (PDE3A) and a decline in oocyte cGMP results in increased PDE3A activity. The ensuing decrease in oocyte cAMP triggers maturation by alleviating the aforementioned phosphorylations of WEE2 and CDC25B. As a direct consequence CDC25B translocates into the nucleus. The resulting activation of CDK1 also promotes extrusion of WEE2 from the nucleus thereby providing a positive amplification mechanism for CDK1 activation. Other kinases, e.g. protein kinase B, Aurora kinase A and polo-like kinase 1, also participate in resumption of meiosis. Mechanisms governing meiotic prophase I arrest and resumption of meiosis share common features with DNA damage-induced mitotic G2-checkpoint arrest and checkpoint recovery, respectively. These common features include CDC14B-dependent activation of APC-CDH1 in prophase I arrested oocytes or G2-arrested somatic cells, and CDC25B-dependent cell cycle resumption in both oocytes and somatic cells.
哺乳动物卵母细胞在减数分裂前期 I 期停滞，直到青春期时，促黄体生成素 (LH) 诱导滤泡内卵母细胞恢复减数分裂。减数分裂的恢复与调控细胞周期蛋白依赖性激酶 1 (CDK1) 的活性密切相关。前期 I 期的阻滞依赖于 CDK1 的抑制性磷酸化和 APC-CDH1 介导的细胞周期蛋白 B 水平的调节。前期 I 期的阻滞由内源性产生的环腺苷单磷酸 (cAMP) 维持，它激活蛋白激酶 A (PKA)，PKA 又磷酸化（并激活）核激酶 WEE2。此外，PKA 介导的磷酸化使 CDC25B 磷酸酶保留在细胞质中。这种联合作用保持 CDK1 活性的低水平，不足以启动减数分裂的恢复。LH 触发壁颗粒细胞中表皮生长因子样因子的合成，并通过缝隙连接导致 cumulus 细胞向卵母细胞的 cGMP 转移减少，缝隙连接连接这两种细胞类型。cGMP 抑制卵母细胞磷酸二酯酶 3A (PDE3A)，卵母细胞 cGMP 的下降导致 PDE3A 活性增加。随之而来的卵母细胞 cAMP 减少通过缓解上述 WEE2 和 CDC25B 的磷酸化来触发成熟。作为直接结果，CDC25B 易位到细胞核中。CDK1 的激活也促进了 WEE2 从细胞核中的释放，从而为 CDK1 的激活提供了一个正的放大机制。其他激酶，如蛋白激酶 B、极光激酶 A 和 polo 样激酶 1，也参与减数分裂的恢复。调控减数分裂前期 I 期阻滞和恢复的机制与 DNA 损伤诱导的有丝分裂 G2 检验点阻滞和检验点恢复分别具有共同的特征。这些共同的特征包括在前期 I 期阻滞的卵母细胞或 G2 期阻滞的体细胞中，CDC14B 依赖性激活 APC-CDH1，以及在卵母细胞和体细胞中，CDC25B 依赖性细胞周期恢复。
