I. Hernandez-munoz et al., The Rgr oncogene (homologous to RalGDS) induces transformation and gene expression by activating Ras, Ral and Rho mediated pathways, ONCOGENE, 19(23), 2000, pp. 2745-2757
The effects of the 5'-truncated Rgr oncogene, previously shown specific gua
nine exchange factor for Ral in vitro, in stimulating proliferation, cell t
ransformation and gene expression were investigated. We have established Te
tRgr cell lines in which expression of Rgr can be inhibited by the presence
of tetracycline in the medium. Using this system, we show that Rgr overexp
ressing cells are morphologically transformed and grow in a disorganized ma
nner. At the transcriptional level, Rgr enhances the activity of the serum
response element and c-Jun. Rgr induces phosphorylation of ERKs, p38 and JN
K kinases, and increases the levels of the GTP-bound forms of Ral and Ras.
I:as activation could account for the broad spectra of effects displayed by
Rgr. The important role of these pathways is confirmed by experiments in w
hich the transcriptional activation events can be blocked by dominant negat
ive versions of Ras, Ral and Rho. Among all the Rgr-induced pathways, the R
as-Raf-MEK-ERK cascade is essential for the transforming properties of Rgr.
Additional analysis has shown that the activation of this pathway by Rgr i
s not due to a feed back mechanism mediated by the Grb2 adaptor protein.