MEMBRANE SIGNAL TRANSDUCTION IN TUMOR PROMOTION

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The overall aim of this research is to identify and characterize gene regulation events that propel rate limiting steps during tumor promotion and tumor progression. The AP-l transcription factor is a heterodimer of Jun and Fos family proteins that binds to a specific sequence on the transcriptional promoter of certain genes and drives their transcription. Our 1989 observation (Bernstein and Colburn, Science, 1989) that promotion sensitive (P+) but not promotion resistant (P-) mouse JB6 cells responded to tumor promoters by activating AP-l dependent transcription, suggested that AP-1 activation might be required for progression from preneoplastic to neoplastic (tumor) phenotype. Initial testing of this hypothesis revealed that the pharmacologic inhibitors, glucocorticoids and retinoids and the "gene therapy" inhibitor dominant negative jun (TAM67) blocked both AP-1 activation and transformation response. This has been extended to show that transcription factor specific retinoids that transrepress AP-l activity without transactivating retinoic acid response element (RARE) dependent gene transcription, also prevent neoplastic transformation (Li et al., Cancer Res, 1996). The dominant negative jun mutant (TAM67) transgene driven by a keratin 14 (Kl4) promoter, when expressed in a mouse keratinocyte line 308 suppressed both AP-l and NFkappaB transcription factor activities as well as induced invasion into matrigel (Dong et al., Molec. Carcinog., in press) suggesting the possible importance of a second transcription factor NFkappaB in both the cause and prevention of progression. Both AP-1 and NFkappaB activities and DNA binding show progressive elevation in a human keratinocyte progression model. When the transgene Kl4-TAM67 is expressed in the more progressed-stage human cell lines that are tumorigenic or anchorage independent, tumor cell phenotype is suppressed (Li et al., in preparation). In vivo extensions are underway. Expression of TAM67 in mouse JB6 P+ cells produced phenotypic reversion to P- phenotype when cells were grown on a graft bed (Strickland et al., in preparation). Transgenic mice expressing the K- 14-TAM67 transgene have been generated. Progeny of two founders will be characterized for possible protection against promotion of skin carcinogenesis, i.e., prevention of premalignant papilloma formation. Thus, targeting transcription factors AP-1 and NFkappaB appears promising for prevention and treatment of cancer.