OBLIGATORY WOUNDING REQUIREMENT FOR TUMORIGENESIS IN V-JUN TRANSGENIC MICE

AVIAN sarcoma virus 17 induces fibrosarcomas in chickens1 and can transform a number of avian cell types in vitro2 by the action of v-jun (refs 1-3). This gene and the related cellular genes c-jun4-6, jun B7 and jun D8,9, encode transactivating (or repressing) DNA-binding proteins that form homo- or heterodimeric (Jun-Jun and Jun-Fos) complexes5,10,11 which recognize the AP-1 consensus sequence TGACTCA (refs 12,13), a response element that confers sensitivity to the tumour-promoting phorbol ester TPA14. We have produced several lines of transgenic mice carrying the v-jun oncogene, driven by the promoter of the widely expressed H-2Kk major histocompatibility complex (MHC) class I antigen gene. Transgenic animals are initially phenotypically normal, but after full-thickness wounding they show abnormal wound repair, characterized by hyperplastic granulation tissue. Many of these lesions are slowly progressive because of continuing fibrob blast proliferation, and over 2-5 months some give rise to dermal fibrosarcomas. This reproducible multistep transition through a proliferative but benign intermediate is associated with characteristic increments in v-jun expression. Moreover, hyperplastic wound repair and its progression are both related to transgene dosage, suggesting that there exists a quantitative requirement or threshold for v-jun action. Our results indicate that v-jun is not oncogenic in transgenic mice as a result of a 'single-hit' mechanism, but rather, in addition to an obligatory wound, that secondary genetic or epigenetic events (possibly conscripting normal constituents of wound repair) are necessary for tumour development and progression. © 1990 Nature Publishing Group.