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

Matthew R. Young, Jian-Jian Li, Mercedes Rincón, Richard A. Flavell, B. K. Sathyanarayana, Rosemarie Hunziker, Nancy Colburn

Research output: Contribution to journalArticle

360 Scopus citations

Abstract

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 keratinocytes. Until now, the question of whether AP-1 transactivation 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 expression 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 inhibit induction of candidate AP-1 target genes, collagenase-1 or stromelysin-3. More interestingly, TAM67 expression did not inhibit TPA- induced hyperproliferation. In two-stage skin carcinogenesis experiments, the transgenic animals showed a dramatic inhibition 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.

Original languageEnglish (US)
Pages (from-to)9827-9832
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number17
DOIs
StatePublished - Aug 17 1999
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • General

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