| ras genes, a large family of small GTPases, play an important role in a variety of signal transduction and differentiation processes, including the regulation of cell proliferation, cell survival, apoptosis, senescence, T-cell activation, cytoskeleton, and vesicle movement. Point mutations in ras genes have been found in a large number and wide variety of human tumors. These oncogenic Ras mutants are locked in an active GTP-bound state that leads to a constitutive and deregulated activation of Ras function. The dogma that ras oncogenes are dominant, whereby the mutation of a single allele in a cell will predispose the host cell to transformation regardless of the presence of the normal allele, is being challenged.; Our results have shown that the N-ras oncogene is not dominant over Ras proto-oncogenes. We have seen that overexpression of large amounts of the N-ras proto-oncogene protects against thymic lymphomagenesis in transgenic mice that express the N-ras oncogene. In addition, increasing amounts of Ras proto-oncogenes are able to compete with the N-ras oncogene in the formation of foci and in the activation of Elk. We have been able to determine that the in vitro competition between Ras proto-oncogenes and the N- ras oncogene occurs first at the effector level at the membrane, then at the processing level, and lastly at the effector level in the cytosol.; We have also determined that the N-ras proto-oncogene can act as a “tumor suppressor,” even in model systems that do not have ras activating mutations. To investigate the inhibitory role of wild-type N-ras in in vitro and in vivo transformation, we introduced wild-type N-ras in N- ras-deficient tumor cells that lack ras activating mutations and found decreased growth in low serum, reduction in the ability for anchorage-independent growth, and a marked inhibition in tumorigenic potential. Taken together, our results show that wildtype N-ras has “tumor suppressor” activity, even in the absence of its oncogenic allele, suggesting that N- ras could be a general inhibitor of the malignant phenotype. |
