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Originally published In Press as doi:10.1074/jbc.M300035200 on January 20, 2003

J. Biol. Chem., Vol. 278, Issue 13, 11041-11049, March 28, 2003
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Regulation of Biglycan Gene Expression by Transforming Growth Factor-beta Requires MKK6-p38 Mitogen-activated Protein Kinase Signaling Downstream of Smad Signaling*

Hendrik UngefrorenDagger , Wolfgang Lenschow, Wen-Bin Chen§, Fred Faendrich, and Holger Kalthoff

From the Research Unit Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, Christian-Albrechts-University, 24105 Kiel, Germany

Several signaling pathways have been implicated in mediating TGF-beta 1-induced extracellular matrix production and fibrosis. We have shown recently that induction of biglycan (BGN) expression by TGF-beta 1 depended on a functional Smad pathway (Chen, W.-B., Lenschow, W., Tiede, K., Fischer, J. W., Kalthoff, H., and Ungefroren, H. (2002) J. Biol. Chem. 277, 36118-36128). Here, we present evidence that the ability of TGF-beta 1 to induce BGN mRNA, in addition to Smads, requires p38 MAPK signaling, because 1) pharmacological inhibitors of p38 dose-dependently inhibited the TGF-beta effect without significantly affecting the transcriptional activity of a constitutively active mutant of the TGF-beta type I receptor or Smad2 phosphorylation at concentrations up to 10 µM, 2) the up-regulation of BGN mRNA was preceded by a delayed increase in the phosphorylation of p38 and its upstream activator MKK6 in TGF-beta 1-treated PANC-1 cells, 3) inhibition of the p38 pathway by stable retroviral transduction with a dominant negative mutant of either p38 or MKK6 reduced TGF-beta 1-induced BGN mRNA expression, and 4) overexpression of wild-type p38 or MKK6, but not MKK3, augmented the TGF-beta 1 effect on BGN mRNA. We further demonstrate that the (delayed) p38 activation by TGF-beta 1 is downstream of Smads and requires a functional Smad pathway, because blocking TGF-beta -induced p38 activity with SB202190 had no effect on Smad2 phosphorylation, but blocking Smad signaling by forced expression of Smad7 abolished TGF-beta 1 induction of p38 activation and, as shown earlier, BGN mRNA expression; finally, re-expression of Smad4 in Smad4-null CFPAC-1 cells restored TGF-beta -induced p38 phosphorylation and, as demonstrated previously, BGN mRNA accumulation. These results clearly show that TGF-beta induction of BGN expression in pancreatic cells requires activation of MKK6-p38 MAPK signaling downstream of Smad signaling and provide a mechanistic clue to the up-regulation of BGN seen in inflammatory response-related fibrosis and desmoplasia.

* This work was supported in part by Deutsche Forschungsgemeinschaft Grant UN 128/1-1 and UN 128/1-2 (to H. U.). Some of the results from this study form part of the doctoral thesis of W. C. and W. L.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Research Unit Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, Christian-Albrechts-University, Arnold-Heller Strasse 7, D-24105 Kiel, Germany. Tel.: 49-0-431-597-2039; Fax: 49-0-431-597-1939; E-mail: hungefroren@email.uni-kiel.de.

§ Present address: The First Affiliated Hospital, Medical College, Zhejiang University, Zhejiang, 310003 Hangzhou, People's Republic of China.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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