CELL-SPECIFIC INDUCTION OF DISTINCT ONCOGENES OF THE JUN FAMILY IS RESPONSIBLE FOR DIFFERENTIAL REGULATION OF COLLAGENASE GENE-EXPRESSION BY TRANSFORMING GROWTH-FACTOR-BETA IN FIBROBLASTS AND KERATINOCYTES

Transforming growth factor-beta (TGF-beta) plays a major role in regul ating connective tissue deposition by controlling both extracellular m atrix production and degradation. In this study, we show that TGF-beta transcriptionally represses both basal and tumor necrosis factor-alph a-induced collagenase (matrix metalloprotease-1) gene expression in de rmal fibroblasts in culture, whereas it activates its expression in ep idermal keratinocytes. We demonstrate that this differential effect of TGF-beta on collagenase gene expression is due to a cell type-specifi c induction of distinct oncogenes of the Jun family, which participate in the formation of AP-1 complexes with different trans-activating pr operties. Specifically, our data indicate that the inhibitory effect o f TGF-beta in fibroblasts is likely to be mediated by jun-B, based on the following observations: (a) TGF-beta induces high levels of jun-B expression and (b) over-expression of jun-B mimics TGF-beta effect in inhibiting basal collagenase promoter activity and preventing tumor ne crosis factor-alpha-induced trans-activation of the collagenase promot er. In contrast, TGF-beta induction of collagenase gene expression in keratinocytes is preceded by transient elevation of c-jun proto-oncoge ne expression. Over-expression of c-jun leads to trans-activation of t he collagenase promoter in both cell types, suggesting that c-jun is a ubiquitous inducer of collagenase gene expression. Transfection of ke ratinocytes with an antisense c-jun construct together with a collagen ase promoter/reporter gene construct inhibits basal and TGF-beta induc ed up-regulation of the collagenase promoter activity, implying that c -jun mediates TGF-beta effect in this cell type. Collectively, our dat a suggest differential signaling pathways for TGF-beta in dermal fibro blasts and epidermal keratinocytes, leading to cell type-specific indu ction of two AP-1 components with opposite transcriptional activities.