Oncogenic activation of human R-ras by point mutations analogous to those of prototype H-ras oncogenes.
R-ras, K-rev-1/rap and TC21, are more closely related to prototype H-ras than any other known members of the ras superfamily. We recently isolated a mutationally activated TC21 oncogene from a human ovarian carcinoma cell line. Based upon these observations, we sought to re-examine the transforming potential of R-ras, which was reported earlier to lack transforming capacity. Mutations were introduced into the R-ras gene at codons 38 or 87, analogous to positions 12 and 61, respectively, responsible for H-ras oncogene activation. While both mutations resulted in acquisition of R-ras transforming capacity for NIH3T3 cells the position 61 was shown to be more active. Transfectants expressing either R-ras mutant formed colonies in soft agar and were tumorigenic in vivo. As has been reported for H-ras, R-ras cooperated with c-raf-1 in inducing transformation of NIH3T3 cells. These results imply interactions in R-ras and c-raf-1 signaling pathways. We observed R-ras transcripts of 4.6 and 1.2 kb ubiquitously expressed in each of a variety of tissues examined. All these findings raise the possibility that R-ras, like prototype ras genes, may be mutationally activated as an oncogene in some human malignancies.
Saez
R
R
Laboratory of Cellular & Molecular Biology, Bethesda, Maryland, MD 20892.
Chan
A M
AM
Miki
T
T
Aaronson
S A
SA
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D017931:DNA Primers; D020558:GTP Phosphohydrolases / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics*; D011905:Genes, ras; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins; D010957:Plasmids; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins
D017931:DNA Primers; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; C087360:RRAS2 protein, human; C490200:Rras2 protein, mouse; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C085929:RRAS protein, human; C513254:Rras protein, mouse; D020559:Monomeric GTP-Binding Proteins; D018631:ras Proteins