Mutant alpha subunits of G12 and G13 proteins induce neoplastic transformation of Rat-1 fibroblasts
Voyno-Yasenetskaya, T.A.; Pace, A.M.; Bourne, H.R.
Oncogene 9(9): 2559-2565
1994
ISSN/ISBN: 0950-9232 PMID: 8058319 Document Number: 432144
Mutationally activated alpha subunits of two G proteins, G-s and G-12, induce neoplastic transformation of fibroblasts and are found in human tumors. Here we report that mutationally activated alpha subunits of two other G proteins, G12 and G13, induce neoplastic transformation of Rat-1 fibroblasts and NIH3T3 fibroblasts. Constitute activation of these alpha subunits resulted from replacement by leucine of glutamine-229 and glutamine-226 in alpha-12 and alpha-13, respectively. Transient expression of mutant alpha-12 and alpha-13 cDNAs induced focus formation in Rat-1 cells and NIH3T3 cells, and stable expression of these mutant proteins in Rat-1 cells accelerated growth rate, induced growth in soft agar, and increased DNA synthesis. Mitogen-activated protein (MAP) kinase activity, stimulated by EGF, was increased in Rat-1 cells that expressed mutant alpha-12 or alpha-13. The MAP kinase cascade plays a role in mediating neoplastic transformation induced by other GTPases, including ras and the alpha subunit of G-12. Therefore, we propose that the MAP kinase cascade is an effector pathway affected by alpha-12 and alpha-13 and may contribute to neoplastic transformation by these mutant proteins. We predict that activating somatic mutations in alpha-12 and alpha-13 genes will be found in human tumors, as is the case for mutationally activated alpha subunits of G-s and G-12.