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Activator Protein 1 Transcription Factors Are Fundamental to v-ras^Ha-induced Changes in Gene Expression in Neoplastic Keratinocytes

Laboratory of Cellular Carcinogenesis and Tumor Promotion [S. E. R., T. L. A., A. G., S. H. Y.] and Laboratory of Metabolism [M. T. B., C. V.], National Cancer Institute, Bethesda, Maryland 20892

The induction of mouse skin papillomas by initiation-promotion protocols is associated with aberrant expression of epithelial markers in the tumor mass. Similarly, initiation of mouse keratinocytes with a retrovirus encoding the v-ras^Ha gene (v-ras^Ha keratinocytes) causes characteristic alterations of epidermal gene expression (A. A. Dlugosz et al., Cancer Res., 54: 6413–6420, 1994). Because activator protein 1 (AP-1) proteins are likely targets of Ras activation, we have examined the role of AP-1 factors in v-ras^Ha keratinocytes. Introduction of v-ras^Ha into keratinocytes up-regulates c-Fos, Fos B, and Fra-1 transcripts and protein levels in nuclear extracts. The expression of Jun proteins is not significantly altered in v-ras^Ha keratinocytes. Transduction of cells with v-ras^Ha results in increased AP-1-dependent transcriptional activity, which is also simulated by transfection of keratinocytes with either c-Fos or Fos B but not Fra-1, suggesting that the up-regulation of c-Fos and Fos B contributes to this effect. To explore the role of AP-1 proteins in regulating keratinocyte markers in v-ras^Ha keratinocytes, we blocked the binding of AP-1 proteins to DNA by infecting keratinocytes with an adenovirus encoding a dominant-negative Fos mutant (A-FOS). A-FOS replaces endogenous Fos proteins in the formation of heterodimers with Jun family members and thus prevents the AP-1 transcription factor from binding to DNA. In v-ras^Ha keratinocytes, the A-FOS virus reversed the suppression of keratins 1 and 10 transcripts and protein, which is characteristically seen in tumors and v-ras^Ha keratinocytes. A-FOS also increased protein levels but reduced transcripts for the late marker, loricrin, a component of the cornified envelope. These findings indicate that AP-1 proteins are involved in the changes in gene expression that define the v-ras^Ha phenotype in mouse keratinocytes.

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