Distinct cell cycle timing requirements for extracellular signal-regulated kinase and phosphoinositide 3-kinase signaling pathways in somatic cell mitosis
Distinct cell cycle timing requirements for extracellular signal-regulated kinase and phosphoinositide 3-kinase signaling pathways in somatic cell mitosis
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DOI：
10.1128/mcb.22.20.7226-7241.2002
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发表时间：
2002-10-01
影响因子：
5.3
通讯作者：
Ahn, NG
中科院分区：
文献类型：
--
作者：
Roberts, EC;Shapiro, PS;Ahn, NG
丝裂原活化蛋白(MAP)和磷脂酰肌醇3-激酶(PI3K)通路是细胞周期进入S时相所必需的，然而，在限制点之后这些通路的重要性却知之甚少。在本研究中，我们研究了细胞外信号调节激酶(ERK)和PI3K在同步化的HeLa和NIH3T3细胞G(2)/M期间的调节和功能。MAPK/ERK和PI3K/Akt通路的磷酸化和激活都发生在S晚期，并持续到有丝分裂结束。在G(2)/M期，PI3K/Akt与ERK通路激活的血清依赖性行为表明，在G(2)/M期，它们的调控机制不同。细胞通透性抑制剂和显性-负性突变体的作用表明，这两条通路都是有丝分裂进程所必需的。然而，抑制PI3K通路会干扰cdc2的激活、细胞周期蛋白B I的表达和有丝分裂的进入，而抑制ERK通路则会干扰有丝分裂的进入，但对cdc2的激活和细胞周期蛋白B1的影响很小，并延缓了从中期到后期的进展。因此，我们的研究为ERK和PI3K通路在G(2)/M期间促进细胞周期进程提供了新的证据，但在不同的时间具有不同的调节机制和功能。
Mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase (PI3K) pathways are necessary for cell cycle progression into S phase; however the importance of these pathways after the restriction point is poorly understood. In this study, we examined the regulation and function of extracellular signal-regulated kinase (ERK) and PI3K during G(2)/M in synchronized HeLa and NIH 3T3 cells. Phosphorylation and activation of both the MAP kinase kinase/ERK and PI3K/Akt pathways occur in late S and persist until the end of mitosis. Signaling was rapidly reversed by cell-permeable inhibitors, indicating that both pathways are continuously activated and rapidly cycle between active and inactive states during G(2)/M. The serum-dependent behavior of PI3K/Akt versus ERK pathway activation indicates that their mechanisms of regulation differ during G(2)/M. Effects of cell-permeable inhibitors and dominant-negative mutants show that both pathways are needed for mitotic progression. However, inhibiting the PI3K pathway interferes with cdc2 activation, cyclin B I expression, and mitotic entry, whereas inhibiting the ERK pathway interferes with mitotic entry but has little effect on cdc2 activation and cyclin B1 and retards progression from metaphase to anaphase. Thus, our study provides novel evidence that ERK and PI3K pathways both promote cell cycle progression during G(2)/M but have different regulatory mechanisms and function at distinct times.