Dudley D T, Pang L, Decker S J, Bridges A J, Saltiel A R
Department of Signal Transduction, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI 48105, USA.
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686-9. doi: 10.1073/pnas.92.17.7686.
Treatment of cells with a variety of growth factors triggers a phosphorylation cascade that leads to activation of mitogen-activated protein kinases (MAPKs, also called extracellular signal-regulated kinases, or ERKs). We have identified a synthetic inhibitor of the MAPK pathway. PD 098059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one] selectively inhibited the MAPK-activating enzyme, MAPK/ERK kinase (MEK), without significant inhibitory activity of MAPK itself. Inhibition of MEK by PD 098059 prevented activation of MAPK and subsequent phosphorylation of MAPK substrates both in vitro and in intact cells. Moreover, PD 098059 inhibited stimulation of cell growth and reversed the phenotype of ras-transformed BALB 3T3 mouse fibroblasts and rat kidney cells. These results indicate that the MAPK pathway is essential for growth and maintenance of the ras-transformed phenotype. Further, PD 098059 is an invaluable tool that will help elucidate the role of the MAPK cascade in a variety of biological settings.
用多种生长因子处理细胞会触发磷酸化级联反应，该反应会导致丝裂原活化蛋白激酶（MAPK，也称为细胞外信号调节激酶或ERK）的激活。我们已经鉴定出一种MAPK途径的合成抑制剂。PD 098059 [2-(2'-氨基-3'-甲氧基苯基)-氧杂萘-4-酮] 选择性抑制MAPK激活酶MAPK/ERK激酶（MEK），而对MAPK本身无明显抑制活性。PD 098059对MEK的抑制作用在体外和完整细胞中均能阻止MAPK的激活以及MAPK底物的后续磷酸化。此外，PD 098059抑制细胞生长刺激，并逆转了ras转化的BALB 3T3小鼠成纤维细胞和大鼠肾细胞的表型。这些结果表明，MAPK途径对于ras转化表型的生长和维持至关重要。此外，PD 098059是一种非常有价值的工具，将有助于阐明MAPK级联反应在各种生物学环境中的作用。
