Induced expression of Rnd3 is associated with transformation of polarized epithelial cells by the Raf-MEK-extracellular signal-regulated kinase pathway

被引:87
作者
Hansen, SH
Zegers, MMP
Woodrow, M
Rodriguez-Viciana, P
Chardin, P
Mostov, KE
McMahon, M
机构
[1] Univ Calif San Francisco, Canc Res Inst, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Sch Med, Dept Anat Biochem & Biophys, San Francisco, CA 94143 USA
[4] CNRS, Inst Pharmacol Mol & Cellulaire, UPR 411, F-06560 Valbonne, France
关键词
D O I
10.1128/MCB.20.24.9364-9375.2000
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Madin-Darby canine kidney (MDCK) epithelial cells transformed by oncogenic Ras and Raf exhibit cell multilayering and alterations in the actin cytoskeleton. The changes in the actin cytoskeleton comprise a loss of actin stress fibers and enhanced cortical actin, Using MDCK cells expressing a conditionally active form of Raf, we have explored the molecular mechanisms that underlie these observations. Raf activation elicited a robust increase in Rad activity consistent with the observed increase in cortical actin, Loss of actin stress fibers is indicative of attenuated Rho function, but no change in Rho-GTP levels was detected following Raf activation, However, the loss of actin stress fibers in Raf-transformed cells was preceded by the induced expression of Rnd3, an endogenous inhibitor of Rho protein function. Expression of Rnd3 alone at levels equivalent to those observed following Raf transformation led to a substantial loss of actin stress fibers. Moreover, tells expressing activated RhoA failed to multilayer in response to Raf, Pharmacological inhibition of MEK activation prevented all of the biological and biochemical changes described above. Consequently, the data are consistent with a role for induced Rnd3 expression downstream of the Raf-MEK-extracellular signal-regulated kinase pathway in epithelial oncogenesis.
引用
收藏
页码:9364 / 9375
页数:12
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