RaIGDS is required for tumor formation in a model of skin carcinoigenesis

To investigate the role of signaling by the small GTPase Rai, we have generated mice deficient for RaIGDS, a guanine nucleotide exchange factor that activates Rai. We show that RaIGDS is dispensable for mouse development but plays a substantial role in Ras-induced oncogenesis. Lack of RaIGDS results in reduced tumor incidence, size, and progression to malignancy in multistage skin carcinogenesis, and reduced transformation by Ras in tissue culture. RaIGDS does not appear to participate in the regulation of cell proliferation, but instead controls survival of transformed cells. Experiments performed in cells isolated from skin tumors suggest that RaIGDS mediates cell survival through the activation of the JNK/SAPK pathway. These studies identify RaIGDS as a key component in Ras-dependent carcinogenesis in vivo.