Normal cellular senescence and cancer susceptibility in mice genetically deficient in Ras-induced senescence-1 (Ris1).

Oncogenic Ras triggers a permanent cell-cycle arrest known as oncogene-induced senescence (OIS) that constitutes a relevant tumor suppressor mechanism. Ris1 (Ras-induced senescence-1) is a novel gene that was identified in a screen as specifically upregulated during Ras-induced senescence, and that is located at a chromosomal region, 3p21.3, frequently lost in human cancer. Moreover, Ris1 is highly conserved in vertebrates, does not present paralogs, and its sequence does not reveal similarities with other proteins or domains. To analyse the physiological function of Ris1 and test its putative role as a tumor suppressor gene, we have generated mutant mice deficient for this gene. Ris1-null mice are viable, fertile, develop normally and do not display any obvious abnormalities. Of relevance, Ris1-deficient mice had a normal lifespan and did not exhibit predisposition to spontaneous tumors or to tumors induced by chemical carcinogens. Finally, Ris1-deficient embryonic fibroblasts were indistinguishable from wild-type cells regarding their proliferation properties, immortalization, senescence and oncogenic transformation. These findings do not support a role of Ris1 in tumor suppression or in OIS.