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J. Biol. Chem., Vol. 281, Issue 42, 31930-31939, October 20, 2006

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The Wilms Tumor Suppressor Wt1 Promotes Cell Adhesion through Transcriptional Activation of the 4integrin Gene^*

Karin M. Kirschner, Nicole Wagner¹, Kay-Dietrich Wagner², Sven Wellmann^¶, and Holger Scholz³

From the Institut für Vegetative Physiologie, Charité-Universitätsmedizin Berlin, Tucholskystrasse 2, 10117 Berlin, Germany, INSERM U636, Centre de Biochimie, Faculté des Sciences, Parc Valrose, 06108 Nice, France, and ^¶Universitäts-Kinderspital Beider Basel, Römergasse 8, 4058 Basel, Switzerland

Cell-matrix interaction through specific adhesion molecules is a critical step during organ development. In addition, down-regulation of cell adhesion receptors may promote tumor invasion and metastasis. We show here that the Wilms tumor suppressor Wt1, which is necessary for normal development of the epicardium, coronary vessels, genitourinary system, and other tissues, activates transcription of the 4integrin gene. Binding of the Wt1(-KTS) form, which is transcriptionally active, to the proximal 4integrin promoter was demonstrated by electrophoretic mobility shift assay and chromatin immunoprecipitation. A reporter construct harboring 1.9 kb of the human 4integrin gene promoter was activated significantly by transient co-transfection of a Wt1(-KTS) expression plasmid. Introducing mutations in two identified Wt1(-KTS) binding motifs in the proximal promoter of the 4integrin gene abrogated this stimulatory effect. Endogenous 4integrin transcripts were increased more than 3-fold in human embryonic kidney 293 cells with stable expression of the Wt1(-KTS) protein. Wt1-overexpressing cells showed augmented adhesion to the 4integrin ligand vascular cell adhesion molecule-1 that was abolished upon incubation with an inhibitory 4integrin antibody. Double immunofluorescent staining revealed co-localization of Wt1 and 4integrin in the developing epicardium of mouse embryos. Cardiac expression of 4integrin was reduced significantly in embryos with a homozygous Wt1 defect (Wt1^-/-). These findings demonstrate that Wt1 can support cell adhesion through enhanced expression of 4integrin. This transcriptional activation of the 4integrin gene by Wt1(-KTS) might contribute to normal formation of the epicardium and other tissues in the developing embryo.

Received for publication, March 21, 2006 , and in revised form, July 24, 2006.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants Scho 634/4-1 and Scho 634/5-1, and by Bundesministerium für Bildung und Forschung Grant NGFN-KGCV1-01GS0416. 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 Recipient of a fellowship from the Deutsche Forschungsgemeinschaft.

² Recipient of a fellowship from European Molecular Biology Organization.

³ To whom correspondence should be addressed. Tel.: 49-30-450-528177; Fax: 49-30-450-528928; E-mail: holger.scholz{at}charite.de.

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