Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway

被引:328
作者
Pumiglia, KM [1 ]
Decker, SJ [1 ]
机构
[1] WARNER LAMBERT PARKE DAVIS,PARKE DAVIS PHARMACEUT RES DIV,DEPT CELL BIOL,ANN ARBOR,MI 48105
关键词
nerve growth factor; MEK inhibitor PD98059; p21(Cip1/WAF1); cell cycle-dependent kinase;
D O I
10.1073/pnas.94.2.448
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:448 / 452
页数:5
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