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Mol Cell Biol, March 1998, p. 1225-1235, Vol. 18, No. 3
Department of
Pharmacology,1
Department of Cell
Biology and Anatomy,4
Curriculum in
Genetics and Molecular Biology,5 and
Lineberger Comprehensive Cancer Center,2
University of North Carolina School of Medicine, Chapel Hill,
North Carolina 27599-7038, and
Onyx Pharmaceuticals, Richmond,
California 948063
Received 24 July 1997/Returned for modification 4 September
1997/Accepted 14 November 1997
The Mas oncogene encodes a novel G-protein-coupled receptor that
was identified originally as a transforming protein when overexpressed
in NIH 3T3 cells. The mechanism and signaling pathways that mediate Mas
transformation have not been determined. We observed that the foci of
transformed NIH 3T3 cells caused by Mas were similar to those caused by
activated Rho and Rac proteins. Therefore, we determined if Mas
signaling and transformation are mediated through activation of a
specific Rho family protein. First, we observed that, like activated
Rac1, Mas cooperated with activated Raf and caused synergistic
transformation of NIH 3T3 cells. Second, both Mas- and Rac1-transformed
NIH 3T3 cells retained actin stress fibers and showed enhanced membrane
ruffling. Third, like Rac, Mas induced lamellipodium formation in
porcine aortic endothelial cells. Fourth, Mas and Rac1 strongly
activated the JNK and p38, but not ERK, mitogen-activated protein
kinases. Fifth, Mas and Rac1 stimulated transcription from common DNA
promoter elements: NF-
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Mas Oncogene Signaling and Transformation Require
the Small GTP-Binding Protein Rac
and
B, serum response factor (SRF), Jun/ATF-2, and
the cyclin D1 promoter. Finally, Mas transformation and some of Mas
signaling (SRF and cyclin D1 but not NF-
B activation) were blocked
by dominant negative Rac1. Taken together, these observations suggest
that Mas transformation is mediated in part by activation of
Rac-dependent signaling pathways. Thus, Rho family proteins are common
mediators of transformation by a diverse variety of oncogene proteins
that include Ras, Dbl family, and G-protein-coupled oncogene proteins.
*
Corresponding author. Mailing address: University of
North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, CB 7295, Chapel Hill, NC 27599-7295. Phone: (919) 966-5634. Fax: (919)
966-0162. E-mail: cjder{at}med.unc.edu.
Present address: Signal Pharmaceuticals, Inc., San Diego, CA
92121.
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