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J. Biol. Chem., Vol. 280, Issue 39, 33190-33199, September 30, 2005

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Adhesion and Rac1-dependent Regulation of Biglycan Gene Expression by Transforming Growth Factor-

EVIDENCE FOR OXIDATIVE SIGNALING THROUGH NADPH OXIDASE^*

From the Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 7, Kiel 24105, Germany

Both transforming growth factor- (TGF-)-induced expression of biglycan (BGN) and activation of p38 MAPK have been implicated in cellular adhesion and migration. Here, we analyzed the role of adhesive events and the small GTPase Rac1 in TGF- regulation of BGN. TGF-1 induction of BGN expression and activation of p38 was abolished or strongly reduced when cells were kept in suspension or exposed to either the actin cytoskeleton-disrupting agent cytochalasin D or a specific chemical Rac1 inhibitor. Ectopic expression of a dominant negative mutant (T17N) of Rac1 abrogated both TGF--induced p38 MAPK activation and BGN up-regulation but did not affect TGF--induced phosphorylation of Smad3 or transcriptional induction of Growth Arrest DNA Damage 45, previously shown to be crucial for TGF- regulation of BGN. Overexpression of wild type Rac1 greatly enhanced the TGF- effect on BGN in adherent cells, whereas ectopic expression of constitutively active Rac1 (Q61L) activated p38 and in the presence of exogenous TGF- was able to rescue BGN expression in nonadherent cells. Endogenous Rac1 was activated by TGF- treatment in PANC-1 cells in an adhesion-dependent fashion. Like Rac1-T17N, the NADPH oxidase inhibitor diphenylene iodonium and the tyrosine kinase inhibitor herbimycin A blocked TGF--induced p38 activation and BGN expression, suggesting that Rac1 exerts its effect on BGN and p38 through increasing NADPH oxidase activity and subsequent production of reactive oxygen species. These results show that the TGF- effect on BGN is dependent on cell adhesion and that activated Rac1, presumably acting through NADPH oxidase(s), is necessary but not sufficient for TGF--induced BGN expression.

Received for publication, April 19, 2005 , and in revised form, July 6, 2005.

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

¹ To whom correspondence should be addressed: Dept. of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 7, 24105 Kiel, Germany. Tel.: 49-431-597-2039; Fax: 49-431-597-1939; E-mail: hungefroren{at}chirurgie-sh.de.

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