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Molecular and Cellular Biology, December 2000, p. 9364-9375, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Induced Expression of Rnd3 Is Associated with Transformation of Polarized Epithelial Cells by the Raf-MEK-Extracellular Signal-Regulated Kinase Pathway†

Steen H. Hansen,1,2,* Mirjam M. P. Zegers,2 Melissa Woodrow,1 Pablo Rodriguez-Viciana,1 Pierre Chardin,3 Keith E. Mostov,2 and Martin McMahon1

Cancer Research Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco Cancer Center,1 and Department of Anatomy, Biochemistry and Biophysics, University of California San Francisco School of Medicine,2 San Francisco, California 94143, and Institut de Pharmacologie Moleculaire et Cellulaire, CNRS UPR 411, 06560 Valbonne, France3

Received 14 June 2000/Returned for modification 21 July 2000/Accepted 20 September 2000

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 Rac1 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, cells 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.

* Corresponding author. Present address: Boston Biomedical Research Institute, 64 Grove St., Watertown, MA 02472-2829. Phone: (617) 658-7940. Fax: (617) 972-1753. E-mail: hansen{at}bbri.org.

dagger This paper is dedicated to Lizzi Nauman.

Molecular and Cellular Biology, December 2000, p. 9364-9375, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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