Cell-specific Induction of Distinct Oncogenes of the Jun Family Is Responsible for Differential Regulation of Collagenase
Gene Expression by Transforming Growth Factor-
in Fibroblasts and Keratinocytes (*)
- Alain Mauviel(1)(3)(§),
- Kee-Yang Chung(1)(3),
- Akhilesh Agarwal(1)(3),
- Katsuto Tamai(1)(3) and
- Jouni Uitto(1)(3)(2)
- From the (1)Departments of Dermatology and Cutaneous Biology and
- (2)Biochemistry and Molecular Biology, Jefferson Medical College and the
- (3)Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
- § To whom correspondence should be addressed: Thomas Jefferson University, Dept. of Dermatology and Cutaneous Biology, 233 South 10th St., Rm. 430, Philadelphia, PA 19107. Tel.: 215-955-5775; Fax: 215-923-9354.
Abstract
Transforming growth factor-β (TGF-β) plays a major role in regulating connective tissue deposition by controlling both extracellular matrix production and degradation. In this study, we show that TGF-β transcriptionally represses both basal and tumor necrosis factor-α-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-β 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-β in fibroblasts is likely to be mediated by jun-B, based on the following observations: (a) TGF-β induces high levels of jun-B expression and (b) over-expression of jun-B mimics TGF-β effect in inhibiting basal collagenase promoter activity and preventing tumor necrosis factor-α-induced trans-activation of the collagenase promoter. In contrast, TGF-β 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-β-induced up-regulation of the collagenase promoter activity, implying that c-jun mediates TGF-β effect in this cell type. Collectively, our data suggest differential signaling pathways for TGF-β in dermal fibroblasts and epidermal keratinocytes, leading to cell type-specific induction of two AP-1 components with opposite transcriptional activities.
Footnotes
-
↵* This work was supported in part by the United States Public Health Service, National Institutes of Health Grants RO1-AR41439 and T32-AR07561 (to J. U.) and by a Dermatology Foundation Research Career Development Award (to A. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵1 The abbreviations used are:
- TNF-α
-
tumor necrosis factor-α
- DMEM
-
Dulbecco's modified Eagle's medium
- GAPDH
-
glyceraldehyde-3-phosphate dehydrogenase
- KGM
-
keratinocyte growth medium
- TGF-β
-
transforming growth factor-β
- CAT
-
chloramphenical acetyltransferase
- PCR
-
polymerase chain reaction
- RSV
-
Rous sarcoma virus
- TRE
-
TPA response element.
-
- Received July 5, 1995.
- Revision received January 16, 1996.
- © 1996 by The American Society for Biochemistry and Molecular Biology, Inc.
