Wildtype Kras2 can inhibit lung carcinogenesis in mice

Although the ras genes have long been established as proto-oncogenes, the d ominant role of activated ras in cell transformation has been questioned. P revious studies have shown frequent loss of the wildtype Kras2 allele in bo th mouse and human lung adenocarcinomas. To address the possible tumor supp ressor role of wildtype Kras2 in lung tumorigenesis, we have carried out a lung tumor bioassay in heterozygous Kras2-deficient mice. Mice with a heter ozygous Kras2 deficiency were highly susceptible to the chemical induction of lung tumors when compared to wildtype mice. Activating Kras2 mutations w ere detected in all chemically induced lung tumors obtained from both wildt ype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhi bited colony formation and tumor development by transformed NIH/3T3 cells a nd a mouse lung tumor cell line containing an activated Kras2 allele. Allel ic loss of wildtype Kras2 was found in 67% to 100% of chemically induced mo use lung adenocarcinomas that harbor a mutant Kras2 allele. Finally, an inv erse correlation between the level of wildtype Kras2 expression and extrace llular signal-regulated kinase (ERK) activity was observed in these cells. These data strongly suggest that wildtype Kras2 has tumor suppressor activi ty and is frequently lost during lung tumor progression.