Continuous ERK activation downregulates anti proliferative genes throughout G1 phase to allow cell-cycle progression
Continuous ERK activation downregulates anti proliferative genes throughout G1 phase to allow cell-cycle progression
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DOI：
10.1016/j.cub.2006.04.044
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发表时间：
2006-06-20
期刊：
影响因子：
9.2
通讯作者：
Nishida, Eisuke
中科院分区：
文献类型：
--
作者：
Yamamoto, Takuya;Ebisuya, Miki;Nishida, Eisuke
背景：MAP激酶的ERK家族在生长因子刺激的细胞周期从G 0/G1期进入S期过程中起着关键作用。有人认为，持续激活，而不是短暂激活，ERK是必要的诱导S期进入。虽然ERK MAP激酶在生长因子刺激的基因表达，特别是即刻早期基因表达中的重要作用已经得到了很好的证实，但ERK活性持续时间如何影响G1期向S期的进展仍不清楚。我们已经发现MEK抑制剂或显性抑制剂对ERK激活的抑制作用，甚至在S期开始之前立即出现负的MEK 1导致S期进入的停止。我们的分析表明，有ERK依赖的下调基因，其表达水平迅速恢复到原来的水平后，ERK失活，他们的下调主要需要AP-1活性。值得注意的是，显微注射实验表明，许多下调的基因作为抗增殖基因在G1期，他们被迫表达的水平之前的生长因子刺激，甚至在G1期后期块S phase entry.Conclusions：因此，连续ERK激活下调抗增殖基因，直到S期的发病，让成功的G1期进展。这种机制也可以作为一种故障安全机制，防止诱导瞬时ERK激活的不适当刺激导致S期进入。
Background: The ERK family of MAP kinase plays a critical role in growth factor-stimulated cell-cycle progression from G0/G1 to S phase. It has been suggested that sustained activation, but not transient activation, of ERK is necessary for inducing S phase entry. Although the essential role of ERK MAP kinase in growth factor-stimulated gene expression, especially expression of immediate-early genes, is well established, it has remained unclear how ERK activity duration affects the promotion of G1 phase progression to S phase.Results: We have found that inhibition of ERK activation by the MEK inhibitor or dominant-negative MEK1 even immediately before the onset of S phase leads to the cessation of S phase entry. Our analyses reveal that there are ERK-dependent downregulated genes, whose expression levels return to their original levels rapidly after ERK inactivation, and that their downregulation mostly requires AP-1 activity. Remarkably, microinjection experiments demonstrate that many of the downregulated genes act as antiproliferative genes during G1 phase and that their forced expression to the levels before growth factor stimulation even in late G1 phase blocks S phase entry.Conclusions: Thus, continuous ERK activation downregulates antiproliferative genes until the onset of S phase to allow successful G1 phase progression. This mechanism may also work as a fail-safe mechanism, which prevents inappropriate stimuli that induce transient ERK activation from causing S phase entry.