COOPERATION BETWEEN V-FOS AND V-RAS(HA) INDUCES AUTONOMOUS PAPILLOMASIN TRANSGENIC EPIDERMIS BUT NOT MALIGNANT CONVERSION

Transgenic mice have been previously established that express v-ras(Ha ) or v-fos exclusively in the epidermis by means of a targeting vector based on the human keratin 1 gene (HK1). Epidermal expression of v-ra s(Ha) (HK1.ras) or v-fos (HK1.fos) resulted in hyperplasia, hyperkerat osis, and later, in benign tumors. To assess the potential for oncogen e cooperation in vivo mating experiments were performed. Resultant HK1 .fos/ras mice exhibited an obvious increase in the severity of neonata l and juvenile preneoplastic phenotypes, together with the immediate o nset of tumorigenesis as compared to single oncogene sibling controls. The HK1.fos/ras tumors grew aggressively and often compromised the an imals by 10-12 weeks. However, tumors remained benign as determined by histotype and specific keratin markers. These data indicate that v-fo s can cooperate with an initiating v-ras(Ha) phenotype to generate aut onomous papillomas, but additional events are required for malignant c onversion.