Sadler Kirsten C, Yüce Ozlem, Hamaratoglu Fisun, Vergé Valérie, Peaucellier Gérard, Picard André
Department of Molecular Biology and Genetics, Bosphorus University, Istanbul, Turkey.
Mol Reprod Dev. 2004 Mar;67(3):366-83. doi: 10.1002/mrd.20023.
The default fate for eggs from many species is death by apoptosis and thus, successful fertilization depends upon suppression of the maternal death program. Little is known about the molecular triggers which activate this process or how the fertilization signal suppresses the default maternal apoptotic pathway. The MAP kinase (MAPK) family member, ERK, plays a universal and critical role in several stages of oocyte meiotic maturation, and fertilization results in ERK inactivation. In somatic cells, ERK and other MAPK family members, p38 and JNK, provide opposing signals to regulate apoptosis, however, it is not known whether MAPKs play a regulatory role in egg apoptosis, nor whether suppression of apoptosis by fertilization is mediated by MAPK activity. Here we demonstrate that MAPKs are involved in starfish egg apoptosis and we investigate the relationship between the fertilization induced signaling pathway and MAPK activation. ERK is active in post-meiotic eggs just until apoptosis onset and then p38, JNK and a third kinase are activated, and remain active through execution. Sequential activation of ERK and p38 is necessary for apoptosis, and newly synthesized proteins are required both upstream of ERK and downstream of p38 for activation of the full apoptotic program. Fertilization causes a dramatic rise in intracellular Ca2+, and we report that Ca2+ provides a necessary and sufficient pro-survival signal. The Ca2+ pathway following fertilization of both young and aged eggs causes ERK to be rapidly inactivated, but fertilization cannot rescue aged eggs from death, indicating that ERK inactivation is not sufficient to suppress apoptosis.
许多物种的卵的默认命运是通过凋亡而死亡，因此，成功受精取决于母体死亡程序的抑制。关于激活这一过程的分子触发因素，或者受精信号如何抑制默认的母体凋亡途径，人们知之甚少。丝裂原活化蛋白激酶（MAPK）家族成员细胞外信号调节激酶（ERK）在卵母细胞减数分裂成熟的几个阶段发挥着普遍而关键的作用，受精会导致ERK失活。在体细胞中，ERK和其他MAPK家族成员p38和JNK提供相反的信号来调节细胞凋亡，然而，尚不清楚MAPK是否在卵凋亡中发挥调节作用，也不清楚受精对凋亡的抑制是否由MAPK活性介导。在这里，我们证明MAPK参与海星卵凋亡，并研究受精诱导的信号通路与MAPK激活之间的关系。ERK在减数分裂后的卵中一直处于活跃状态，直到凋亡开始，然后p38、JNK和第三种激酶被激活，并在整个凋亡执行过程中保持活跃。ERK和p38的顺序激活是凋亡所必需的，并且在ERK上游和p38下游都需要新合成的蛋白质来激活完整的凋亡程序。受精导致细胞内Ca2+急剧升高，我们报告Ca2+提供了一个必要且充分的促生存信号。年轻卵和老化卵受精后的Ca2+途径都会导致ERK迅速失活，但受精不能挽救老化卵免于死亡，这表明ERK失活不足以抑制凋亡。
