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

Activator protein-1 (AP-1) is a transcription factor that consists of eithe r a Jun-Jun homodimer or a Jun-Fos heterodimer, Transactivation of AP-1 is required for tumor promoter-induced transformation in mouse epidermal JB6 c ells and for progression in mouse and human keratinocytes, Until now, the q uestion of whether AP-1 transactivation is required for carcinogenesis in v ivo has remained unanswered, as has the issue of functionally significant t arget genes. To address these issues we have generated a transgenic mouse i n which transactivation mutant c-jun (TAM67), under the control of the huma n keratin-14 promoter, is expressed specifically in the basal cells of the epidermis where tumor induction is initiated. The keratin-14-TAM67 transgen e was expressed in the epidermis, tongue, and cervix, with no apparent abno rmalities in any tissue or organ, TAM67 expression blocked 12-O-tetradecano ylphorbol 13-acetate (TPA, phorbol 12-tetradecanoate 13-acetate) induction of the AP-1-regulated luciferase in AP-1 luciferase/TAM67 mice, but did not inhibit induction of candidate AP-1 target genes, collagenase-1 or stromel ysin-3, More interestingly, TAM67 expression did not inhibit TPA-induced hy perproliferation. In two-stage skin carcinogenesis experiments, the transge nic animals showed a dramatic inhibition of papilloma induction. We conclud e that transactivation of a subset of AP-l-dependent genes is required for tumor promotion and may be targeted for cancer prevention.