Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation
Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation
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Raf/丝裂原激活蛋白激酶独立途径的致癌 Ras 激活足以引起致瘤转化
DOI：
10.1128/mcb.16.7.3923
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发表时间：
1996
影响因子：
5.3
通讯作者：
C. Der
中科院分区：
文献类型：
--
作者：
R. Khosravi‐Far;M. White;J. Westwick;P. A. Solski;M. Chrzanowska;L. Aelst;M. Wigler;C. Der
大量证据支持Raf-1/MEK/丝裂原活化蛋白激酶途径在致癌Ras介导的转化中的活化的关键作用。例如，Raf-1、MEK和促分裂原活化蛋白激酶的显性失活突变体都抑制Ras转化。此外，质膜定位的Raf-1表现出与致癌Ras相同的转化潜能的观察结果表明，Raf-1单独活化足以介导完整的Ras转化活性。然而，最近对其他候选Ras效应物的鉴定（例如，RalGDS和磷脂酰肌醇-3激酶）表明其他下游效应子介导的信号传导途径的激活也可能介导Ras转化活性。在支持这一点，两个H-Ras效应结构域突变体，H-Ras（12 V，37 G）和H-Ras（12 V，40 C），这是缺陷的Raf结合和激活，诱导有效的致瘤转化的NIH 3 T3成纤维细胞的一些菌株。这些Raf-binding缺陷型突变体的H-Ras诱导的形态转化，这是无法区分的Rho家族蛋白的激活成员诱导。此外，这两个突变体的转化活性协同增强激活Raf-1和抑制显性负RhoA（19 N）突变体，表明Ras可能会导致转化发生通过协调激活的Raf-dependent和-independent途径，涉及Rho家族蛋白。最后，H-Ras（12 V，37 G）和H-Ras（12 V，40 C）的共转染导致其焦点形成活性的协同合作，表明Ras激活至少两个Raf-independent的Ras效应子介导的信号传导事件。
Substantial evidence supports a critical role for the activation of the Raf-1/MEK/mitogen-activated protein kinase pathway in oncogenic Ras-mediated transformation. For example, dominant negative mutants of Raf-1, MEK, and mitogen-activated protein kinase all inhibit Ras transformation. Furthermore, the observation that plasma membrane-localized Raf-1 exhibits the same transforming potency as oncogenic Ras suggests that Raf-1 activation alone is sufficient to mediate full Ras transforming activity. However, the recent identification of other candidate Ras effectors (e.g., RalGDS and phosphatidylinositol-3 kinase) suggests that activation of other downstream effector-mediated signaling pathways may also mediate Ras transforming activity. In support of this, two H-Ras effector domain mutants, H-Ras(12V, 37G) and H-Ras(12V, 40C), which are defective for Raf binding and activation, induced potent tumorigenic transformation of some strains of NIH 3T3 fibroblasts. These Raf-binding defective mutants of H-Ras induced a transformed morphology that was indistinguishable from that induced by activated members of Rho family proteins. Furthermore, the transforming activities of both of these mutants were synergistically enhanced by activated Raf-1 and inhibited by the dominant negative RhoA(19N) mutant, indicating that Ras may cause transformation that occurs via coordinate activation of Raf-dependent and -independent pathways that involves Rho family proteins. Finally, cotransfection of H-Ras(12V, 37G) and H-Ras(12V, 40C) resulted in synergistic cooperation of their focus-forming activities, indicating that Ras activates at least two Raf-independent, Ras effector-mediated signaling events.
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Ras 转化的生物学测定。
影响因子：
--
作者：
Clark,GJ;Cox,AD;Graham,SM;Der,CJ
通讯作者：
Der,CJ
影响因子：
56.9
作者：
MOODIE, SA;WILLUMSEN, BM;WOLFMAN, A
通讯作者：
WOLFMAN, A
Ras 介导的转录激活：通过瞬时共转染测定进行分析。
影响因子：
--
作者：
Hauser,CA;Westwick,JK;Quilliam,LA
通讯作者：
Quilliam,LA
影响因子：
56.9
作者：
MANSOUR, SJ;MATTEN, WT;AHN, NG
通讯作者：
AHN, NG
DOI：
10.1073/pnas.91.13.6030
发表时间：
1994-06-21
影响因子：
11.1
作者：
WESTWICK, JK;COX, AD;BRENNER, DA
通讯作者：
BRENNER, DA