Cell-cycle arrest by PD184352 requires inhibition of extracellular signal-regulated kinases (ERK) 1/2 but not ERK5/BMK1
Cell-cycle arrest by PD184352 requires inhibition of extracellular signal-regulated kinases (ERK) 1/2 but not ERK5/BMK1
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DOI：
10.1042/bj20020372
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发表时间：
2002-09-01
影响因子：
4.1
通讯作者：
Cook, SJ
中科院分区：
文献类型：
--
作者：
Squires, MS;Nixon, PM;Cook, SJ
血清和生长因子激活典型的细胞外信号调节激酶 (ERK) 1/2 通路和 ERK5/大丝裂原激活蛋白激酶 1 (BMK) 1 通路。使用 PD98059 和 U0126 对 ERK1/2 通路进行药理学抑制可防止细胞周期蛋白 D1 表达并抑制细胞增殖，认为 ERK1/2 通路是细胞周期重新进入的速率限制。然而，PD98059和U0126也抑制ERK5/BMK1通路，这增加了此类药物的抗增殖作用可能是由于抑制ERK5或两条通路所致的可能性。在这里，我们描述了新型丝裂原激活蛋白激酶/ ERK 激酶 (MEK) 抑制剂 PD184352 对中国仓鼠成纤维细胞系 CC139 中 ERK1/2 和 ERK5 通路的影响。在静止细胞中，血清刺激的 ERK1 活性被 PD184352 完全抑制，IC50 低于 1 μM，而 ERK5 激活即使在 20 μM 时也不受影响。低剂量的 PD184352 可抑制血清刺激的 DNA 合成和细胞周期蛋白 D I 表达，从而消除 ERK1 活性，但对 ERK5 没有影响。同样，在循环细胞中，低剂量时，PD184352 会引起剂量依赖性 G、细胞周期蛋白 D1 表达的抑制和抑制，从而抑制 ERK1，但对 ERK5 没有影响。这些结果表明PD184352的抗增殖作用是由于抑制经典的ERK1/2途径，而不需要抑制ERK5途径。
Serum and growth factors activate both the canonical extracellular signal-regulated kinase (ERK) 1/2 pathway and the ERK5/big mitogen-activated protein kinase 1 (BMK) 1 pathway. Pharmacological inhibition of the ERK1/2 pathway using PD98059 and U0126 prevents cyclin D1 expression and inhibits cell proliferation, arguing that the ERK1/2 pathway is rate limiting for cell-cycle re-entry. However, both PD98059 and U0126 also inhibit the ERK5/BMK1 pathway, raising the possibility that the anti-proliferative effect of such drugs may be due to inhibition of ERK5 or both pathways. Here we characterize the effect of the novel mitogen-activated protein kinase/ ERK kinase (MEK) inhibitor, PD184352, on the ERK1/2 and ERK5 pathways in the Chinese hamster fibroblast cell line CC139. In quiescent cells, serum-stimulated ERK1 activity was completely inhibited by PD184352 with an IC50 below 1 muM, whereas ERK5 activation was unaffected even at 20 muM. Serum-stimulated DNA synthesis and cyclin D I expression was inhibited by low doses of PD184352, which abolished ERK1 activity but had no effect on ERK5. Similarly, in cycling cells PD184352 caused a dose-dependent G, arrest and inhibition of cyclin D1 expression at low doses, which inhibited ERK1 but were without effect on ERK5. These results indicate that the antiproliferative effect of PD184352 is due to inhibition of the classical ERK1/2 pathway and does not require inhibition of the ERK5 pathway.