TUMORIGENIC ACTIVITY OF RHO GENES FROM APLYSIA-CALIFORNICA

rho genes have been found in both lower and higher eucaryotes. They co de for proteins of 21 kDa, highly conserved in evolution, which belong to the superfamily of ras GTPases. Among the members of this superfam ily there are proteins with a regulatory function, such as ras, and pr oteins involved in vesicular trafficking, such as the family of rab pr oteins. We have investigated the putative role of rho proteins from Ap lysia californica as transforming GTPases utilizing the wild-type and a Val-14 mutant, equivalent to the oncogenic Val-12 mutation of ras ge nes found in animal and human tumors. Overexpression of either rho gen e was sufficient to confer anchorage- and serum-independent growth. Mo reover, when introduced into nude mice, selected clones generated from either gene were able to induce tumors, although those carrying the m utated version were more efficient. Pathological analysis indicated th at generated tumors corresponded to well-differentiated fibrosarcomas with distinct and intersecting bundles and spindle cells. By contrast, ras-induced tumors were poorly differentiated fibrosarcomas. Thus, ou r results indicate that under appropriate conditions rho genes functio n as oncogenes and may have a role in the regulation of proliferation in fibroblast cells.