ras Genes and Human Cancer: Different Implications and Different Roles

Jose   M.   Rojas; Eugenio      Santos

Abstract

The human ras genes (Nras, Hras, and Kras) code for closely related small GTPases possessing a molecular size of about 21 KDa. Ras proteins operate as molecular switches in signal transduction cascades controlling cell proliferation, differentiation or apoptosis. As for all G proteins, the function of the ras gene protein products is controlled through a regulated GDP / GTP cycle. Each of the three human ras proto-oncogenes can give rise to a transforming oncogene via single base pair mutations. Mutations at codons 12, 13 or 61 significantly downgrade the GTPase ability of the resulting mutant Ras proteins, which are thus rendered constitutively active and able to transform mammalian cells. Indeed, the detection of such mutations in various human tumors indicates that deregulated GTP binding to Ras is involved in the development of up 30% of all human cancers. Specific members of the Ras family are mutated in different tumor types, with mutations in Kras appearing most frequently. Some tumor cell lines harbor amplified ras genes and transfection studies have shown that a 20-fold increase in the level of expressed normal Ras protein is sufficient to induce transformation of some recipient cells. Studies with knockout mice strains have revealed that Kras (but not Nras or Hras) is necessary and sufficient for the development of the animals to the adult stage. It remains unclear whether the different Ras family members play totally specific or overlapping functional roles in the cell. Recent data on localization to different plasma membrane subdomains, marked quantitative differences of effector activation levels and new roles for some docking / scaffold proteins point to signaling specificities of the different Ras proteins. This review analyzes the current understanding of Ras function focusing on the possible physiological and oncogenic specificities of each Ras family member.

Keywords: ras gene, nras,hras,kras, ras protein, photo-oncogene

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