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J Biol Chem, Vol. 273, Issue 27, 16739-16747, July 3, 1998
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From the The dbl family of oncogenes encodes a
large, structurally related, family of growth-regulatory molecules that
possess guanine nucleotide exchange factor activity for specific
members of the Rho family of Ras-related GTPases. We have evaluated
matched sets of weakly and strongly transforming versions of five Dbl
family proteins (Lfc, Lsc, Ect2, Dbl, and Dbs) to determine their
ability to stimulate signaling pathways that are activated by Rho
family proteins. We found that the transforming potential of this panel did not correlate directly with their ability to activate Jun NH2-terminal kinase, p38/Mpk2, serum response factor, or
c-Jun. In contrast, transient stimulation of transcription from the
cyclin D1 promoter provided a strong correlation with transforming
potential, and we found constitutive up-regulation of cyclin D1 protein
in Dbl family protein-transformed cells. In addition, we observed that
at least two Dbl family members (Lfc and Ect2) induced changes in the
actin cytoskeleton and exhibited nuclear signaling profiles that are
consistent with a broader range of in vivo substrate utilization than is predicted from their in vitro exchange
specificities. In summary, although Dbl family proteins exhibit
signaling profiles that are consistent with their in vivo
activation of Rho proteins, stimulation of cyclin D1 transcription is
the only activity that correlates with transforming potential, thus
suggesting that deregulated cell cycle progression may be important for
Dbl family protein transformation.
Department of Pharmacology and Lineberger
Comprehensive Cancer Center, University of North Carolina School of
Medicine, Chapel Hill, North Carolina 27599-7038, the ¶ Albert
Einstein Cancer Center, Department of Medicine and Department of
Developmental and Molecular Biology, Albert Einstein College of
Medicine, Bronx, New York 10461, and ** Onyx Pharmaceuticals,
Richmond, California 94806
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