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Molecular and Cellular Biology, December 2000, p. 9364-9375, Vol. 20, No. 24
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.
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
*
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.
This paper is dedicated to Lizzi Nauman.
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