A SYNTHETIC INHIBITOR OF THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE
A SYNTHETIC INHIBITOR OF THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE
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DOI：
10.1073/pnas.92.17.7686
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发表时间：
1995-08-15
影响因子：
11.1
通讯作者：
SALTIEL, AR
中科院分区：
文献类型：
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作者：
DUDLEY, DT;PANG, L;SALTIEL, AR
用多种生长因子处理细胞会触发磷酸化级联反应，导致促分裂原活化蛋白激酶（MAPK，也称为细胞外信号调节激酶或ERK）活化。我们已经确定了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MAPK本身无显著抑制活性。PD 098059对MEK的抑制阻止了体外和完整细胞中MAPK的活化和随后MAPK底物的磷酸化。此外，PD 098059抑制细胞生长刺激并逆转ras转化的BALB 3 T3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是必不可少的。此外，PD 098059是一个非常宝贵的工具，将有助于阐明MAPK级联反应在各种生物学环境中的作用。
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.