title: 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.
abstract: Transforming growth factor-beta (TGF-beta) plays a major role in regulating connective tissue deposition by controlling both extracellular matrix production and degradation. In this study, we show that TGF-beta transcriptionally represses both basal and tumor necrosis factor-alpha-induced collagenase (matrix metalloprotease-1) gene expression in dermal fibroblasts in culture, whereas it activates its expression in epidermal keratinocytes. We demonstrate that this differential effect of TGF-beta on collagenase gene expression is due to a cell type-specific induction of distinct oncogenes of the Jun family, which participate in the formation of AP-1 complexes with different trans-activating properties. Specifically, our data indicate that the inhibitory effect of 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 necrosis factor-alpha-induced trans-activation of the collagenase promoter. In contrast, TGF-beta induction of collagenase gene expression in keratinocytes is preceded by transient elevation of c-jun proto-oncogene expression. Over-expression of c-jun leads to trans-activation of the collagenase promoter in both cell types, suggesting that c-jun is a ubiquitous inducer of collagenase gene expression. Transfection of keratinocytes with an antisense c-jun construct together with a collagenase promoter/reporter gene construct inhibits basal and TGF-beta-induced up-regulation of the collagenase promoter activity, implying that c-jun mediates TGF-beta effect in this cell type. Collectively, our data suggest differential signaling pathways for TGF-beta in dermal fibroblasts and epidermal keratinocytes, leading to cell type-specific induction of two AP-1 components with opposite transcriptional activities.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia, Pennsylvania, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mauviel
authors.forename: K Y
authors.initials: KY
authors.lastname: Chung
authors.forename: A
authors.initials: A
authors.lastname: Agarwal
authors.forename: K
authors.initials: K
authors.lastname: Tamai
authors.forename: J
authors.initials: J
authors.lastname: Uitto
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002478:Cells, Cultured; D017364:Collagenases / Q000235:genetics*; D005347:Fibroblasts / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D016758:Genes, jun; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology*; D051379:Mice; D016376:Oligonucleotides, Antisense; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: C000715470:MAS1 protein, human; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D016212:Transforming Growth Factor beta; D017364:Collagenases