Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway
Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway
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DOI：
10.1073/pnas.94.2.448
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发表时间：
1997-01-21
影响因子：
11.1
通讯作者：
Decker, SJ
中科院分区：
文献类型：
--
作者：
Pumiglia, KM;Decker, SJ
丝裂原激活蛋白激酶 (MAPK) 级联在将细胞外信号转导为控制生长和分化的反应中发挥着至关重要的作用。已经检查了 MAPK 激酶 (MEK)/MAPK 通路的特定抑制剂 (PD98059) 对神经生长因子 (NGF) 诱导的生长停滞和细胞周期依赖性激酶 (CDK) 抑制的影响。用 PD98059 处理表达 TRKA 的 NIH 3T3 细胞，显着逆转了 NGF 对这些细胞生长的完全抑制。 PD98059 还阻断 NGF 抑制 CDK4 和 CDK2 活性的能力，同时部分阻止 NGF 诱导 p21(Cip1/WAF1)。为了独立评估 MEK/MAPK 通路在生长停滞中的参与，在这些细胞中表达了 Raf-1 原癌基因 (Delta RAF-1:ER) 的诱导激活形式。 Delta RAF-1:ER 的激活导致这些细胞的 MAPK 活性长期增加和生长停滞，同时诱导 p21(Cip1/WAF1) 并抑制 CDK2 活性。用 PD98059 处理细胞可逆转 Delta RAF-1:ER 激活的这些影响。这些数据表明，除了作为生长的正效应器外，MEK/MAPK 途径的刺激还可导致 CDK 活性的抑制和细胞周期停滞。
The mitogen-activated protein kinase (MAPK) cascade plays a crucial role in the transduction of extracellular signals into responses governing growth and differentiation. The effects of a specific inhibitor of the MAPK kinase (MEK)/MAPK pathway (PD98059) on nerve;growth factor (NGF)-induced growth arrest and inhibition of cell cycle-dependent kinases (CDKs) have been examined. Treatment of NIH 3T3 cells expressing TRKA with PD98059 dramatically reversed the complete inhibition of growth of these cells caused by NGF. PD98059 also blocked the ability of NGF to inhibit the activities of CDK4 and CDK2, while partially preventing NGF induction of p21(Cip1/WAF1). To independently evaluate the involvement of the MEK/MAPK pathway in growth arrest, an inducible activated form of the Raf-1 protooncogene (Delta RAF-1:ER) was expressed in these cells. Activation of Delta RAF-1:ER resulted in a prolonged increase in MAPK activity and growth arrest of these cells, with concomitant induction of p21(Cip1/WAF1) and inhibition of CDK2 activity, These effects of Delta RAF-1:ER activation were all reversed by treatment of cells with PD98059, These data indicate that in addition to functioning as a positive effector of growth, stimulation of the MEK/MAPK pathway can result in an inhibition of CDK activity and cell cycle arrest.