Transgenic coexpression of v-Ha-ras and transforming growth factor α increases epidermal hyperproliferation and tumorigenesis and predisposes to malignant conversion via endogenous c-Ha-ras activation

✍ Scribed by Xiao-Jing Wang; David A. Greenhalgh; Dennis R. Roop

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 831 KB
• Volume: 27
• Category: Article
• ISSN: 0899-1987
• DOI: 10.1002/(sici)1098-2744(200003)27:3<200::aid-mc7>3.0.co;2-9

✦ Synopsis

Previously, transgenic mice were generated that overexpressed v-Ha-ras or human transforming growth factor a (TGFa) exclusively in the epidermis, by means of a targeting vector based on the human keratin 1 gene (HK1). Both transgenics exhibited a similar neonatal phenotype of epidermal hyperplasia/hyperkeratosis and, in adults, spontaneous and 12-O-tetradecanoylphorbol-13-acetate (TPA)±induced papilloma formation. To assess the synergism in vivo between Ha-ras and TGFa, mating experiments were performed. All ras/TGFa double genotype progeny (HK1.ras/a) exhibited an increased epidermal hyperplasia/hyperkeratosis in neonates and accelerated spontaneous papillomatogenesis, compared with single transgenic siblings. HK1.ras/a mice from the mild lines of HK1.ras  HK1.TGFa developed spontaneous papillomas that were not shown in either their parental mice or single transgenic littermates. Unlika in parental or single-genotype siblings, in which TPA promotion-elicited papillomas remained benign, TPA promotion elicited autonomous papillomas in HK1.ras/a mice and exhibited a novel susceptibility to malignant conversion. Sequence analysis of the endogenous c-Ha-ras from spontaneous and TPAinduced HK1.ras/a papillomas revealed wild-type sequence. However, carcinomas exhibited c-Ha-ras mutations at codon 61. All tumors analyzed to date expressed wild-type p53. These data provide in vivo evidence that Ha-ras and TGFa cooperate in the induction of epidermal hyperplasia and spontaneous tumor formation and predispose to malignant conversion via endogenous c-Ha-ras activation.