Transgenic mice demonstrate AP-1 (activator protein-1 ) transactivation is reqiured for tumor promotion

摘要

Activator protein-1 (AP-1) is a transcription factor that consists of either a Jun-Jun homodimer or a Jun-Fos heterodimer. Transactivation of AP-1 is required for tumor promoter-induced transformation in mouse epidermal JB6 cells and for progression in mouse and human keratin- ocytes. Until uow, tbe question of whether AP-1 transactiva- tion is required for carcinogenesis in vivo has remained unanswered, as has the issue of functionally significant target genes. To address these issues we have generated a transgenic mouse in which transactivation mutant c-jun (TAM67), under the control of the human keratin-14 promoter, is expressed specifically in the basal cells of the epidermis where tumor induction is initiated. The keratin-14-TAM67 transgene was expressed in the epidermis, tongue, and cervix with no apparent abnormalities in any tissue or organ. TAM67 ex- pression blocked 12-O-tetradecanoylphorbol 13-acetate (TPA phorbol 12-tetradecanoate 13-acetate) induction of the AP-1- regulated luciferase in AP-1 luciferase/TAM67 mice, but did not inbibit induction of candidate AP-1 target genes, colla- genase-1 or stromelysin-3. More interestingly, TAM67 expres- sion did not inhibit TPA-induced hyperproliferation. In two- stage skin carcinogenesis experiments, the transgenic animals showed a dramatic inhihition of papilloma induction. We conclude that transactivation of a subset of AP-1-dependent genes is required for tumor promotion and may be targeted for cancer prevention.