KINETICS OF WOUND-INDUCED V-HA-RAS TRANSGENE EXPRESSION AND PAPILLOMADEVELOPMENT IN TRANSGENIC TG.AC MICE

The Tg.AC transgenic mouse, which harbors an activated v-Ha-ras coding region that is fused to an embryonic zeta globin transcriptional cont rol region and a 3' simian virus 40 polyadenylation sequence, rapidly develops epidermal papillomas in response to topical application of ch emical carcinogens or tumor promoters or to full-thickness wounding of the dorsal skin. In this report, we investigated the localization and temporal induction of v-Ha-ras transgene expression after full-thickn ess wounding of Tg.AC mouse skin. Surgically inflicted full-thickness incisions 3 cm long yielded four to six papillomas per Tg.AC mouse by 5 wk after wounding. Similar wounding of the FVB/N isogenic host strai n did not produce tumors, which implicates a causal role for the v-Ha- ras transgene. Reverse transcription-polymerase chain reaction assays detected the v-Ha-ras transgene transcript in total RNA samples isolat ed from wound-associated tissue 3 and 4 wk after wounding. Tissues 1-2 wk after wounding and all non-wound-associated tissues were negative for transgene expression. In situ hybridization experiments using tran sgene-specific S-35-labeled antisense RNA probes localized transgene e xpression to the basal epidermal cells in wound-induced papillomas. Ad jacent normal and hyperplastic skin tissues were negative for transgen e expression by this assay. This work supports the hypothesis that the wound repair response leads to the transcriptional activation and con tinued expression of the v-Ha-ras transgene in specific cells in the s kin, which alters normal epithelial differentiation and ultimately res ults in neoplastic growth. (C) 1997 Wiley-Liss, Inc.dagger