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-1 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 transformation sensitive (P+) but not transformation resistant (P-) mouse JB6 cells responded to tumor promoters by activating AP-1 dependent transcription, suggested that AP-1 activation might be required for progression from preneoplastic to neoplastic(tumor)phenotype. 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 specific retinoids that transrepress AP-1 activity without transactivating retinoic acid response element (RARE) dependent gene transcription, also prevent neoplastic transformation (Li et al., Cancer Res, 1996). Surprisingly TPA induced, but not tumor necrosis factor alpha induced, AP-1 is sensitive to transrepression by retinoid. The limiting molecular interaction governing this sensitivity difference appears to involve cJun (Li et, Cancer Res 1997). The dominant negative jun mutant(TAM67) transgene driven by a keratin 14(K14)promoter, when expressed in a mouse keratinocyte line 308 suppressed both AP-1 and NFkB transcription factor activities as well as induced invasion into matrigel (Dong et al., Molec. Carcinog.,1997)suggesting the possible importance of a second transcription factor NFkB in both the cause and prevention of progression. Both AP-1 and NFkB activities and DNA binding show progressive elevation in a human keratinocyte progression model. When the transgene K14-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., submitted to Oncogene). Expression of TAM67 in mouse JB6 P+ cells produced phenotypic reversion to P- phenotype when cells were grown on a nude mouse graft bed (Strickland et al., Carcinog. 1997). Transgenic mice expressing the K- 14-TAM67 transgene have been generated. These K14-TAM 67 mice have now been shown in two DMBA-TPA initiation-promotion skin carcinogenesis experiments to show 95% protection against promotion of skin carcinogenesis, i.e., prevention of premalignant papilloma formation. (Young et al., Ms in preparation). Recently we have found that the transformation resistance of a JB6 P- variant is due to a shortage of the MAPK kinases Erks 1 and 2 which are also limiting for AP-1 transactivation (Huang, et al, PNAS, in press). Thus the observation that targetting AP-1 and NFkB elevation prevents tumor promotion and progression has been extended from the mouse JB6 model to mouse and human keratinocyte progression models, and to grafting and transgenic mouse models. New understanding of limiting molecular interactions is emerging.
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