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J. Biol. Chem., Vol. 277, Issue 48, 46338-46346, November 29, 2002

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Smad3 Mediates Transforming Growth Factor--induced Collagenase-3 (Matrix Metalloproteinase-13) Expression in Human Gingival Fibroblasts
EVIDENCE FOR CROSS-TALK BETWEEN Smad3 AND p38 SIGNALING PATHWAYS^*

Suvi-Katri Leivonen^§, Andrew Chantry^¶, Lari Häkkinen, Jiahuai Han^**, and Veli-Matti Kähäri^§

From the  Centre for Biotechnology, University of Turku and Åbo Akademi University, FIN-20520 Turku, Finland, the ^§ Department of Medical Biochemistry and Department of Dermatology, University of Turku, FIN-20520, Turku, Finland, the ^¶ School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, United Kingdom, the  Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada, the ^** Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

Transforming growth factor- (TGF-) is a potent inducer of collagenase-3 (MMP-13) gene expression in human gingival fibroblasts, and this requires activation of the p38 mitogen-activated protein kinase pathway. Here, we have constructed recombinant adenoviruses harboring genes for hemagglutinin-tagged Smad2, Smad3, and Smad4 and used these in dissecting the role of Smads, the signaling mediators of TGF-, in regulation of endogenous MMP-13 gene expression in human gingival fibroblasts. Adenoviral expression of Smad3, but not Smad2, augmented the TGF--elicited induction of MMP-13 expression. In addition, adenoviral gene delivery of dominant negative Smad3 blocked the TGF--induced MMP-13 expression in gingival fibroblasts. Co-expression of Smad3 with constitutively active MKK3b and MKK6b, the upstream activators of p38, resulted in nuclear translocation of Smad3 in the absence of TGF- and in induction of MMP-13 expression. The induction of MMP-13 expression by Smad3 and constitutively active mutants of MKK3b or MKK6b was blocked by specific p38 inhibitor SB203580 and by the dominant negative form of p38. These results show that TGF--induced expression of human MMP-13 gene in gingival fibroblasts is dependent on the activation of two distinct signaling pathways (i.e. Smad3 and p38). In addition, these findings provide evidence for a novel type of cross-talk between Smad and p38 mitogen-activated protein kinase signaling cascades, which involves activation of Smad3 by p38.

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