Yamamoto Takuya, Ebisuya Miki, Ashida Fumito, Okamoto Kazuo, Yonehara Shin, Nishida Eisuke
Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
Curr Biol. 2006 Jun 20;16(12):1171-82. doi: 10.1016/j.cub.2006.04.044.
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.
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.
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.
丝裂原活化蛋白激酶(MAP激酶)的细胞外信号调节激酶(ERK)家族在生长因子刺激的从G0/G1期到S期的细胞周期进程中起关键作用。有人提出,ERK的持续激活而非瞬时激活对于诱导进入S期是必要的。尽管ERK MAP激酶在生长因子刺激的基因表达,尤其是即早基因的表达中所起的重要作用已得到充分证实,但ERK活性持续时间如何影响从G1期到S期进程的促进作用仍不清楚。
我们发现,即使在S期开始前立即用MEK抑制剂或显性负性MEK1抑制ERK激活,也会导致进入S期的停止。我们的分析表明,存在ERK依赖性下调基因,其表达水平在ERK失活后迅速恢复到原始水平,并且它们的下调大多需要AP-1活性。值得注意的是,显微注射实验表明,许多下调基因在G1期作为抗增殖基因起作用,并且即使在G1期末期将它们的表达强制恢复到生长因子刺激前的水平也会阻止进入S期。
因此,持续的ERK激活会下调抗增殖基因,直到S期开始,以允许成功的G1期进程。这种机制也可能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进入S期。