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J. Biol. Chem., Vol. 280, Issue 44, 37266-37277, November 4, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/44/37266    most recent M411580200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fischer, C. Articles by Rosewicz, S. Search for Related Content PubMed PubMed Citation Articles by Fischer, C. Articles by Rosewicz, S. Social Bookmarking                      What's this?

Galectin-1 Interacts with the 51 Fibronectin Receptor to Restrict Carcinoma Cell Growth via Induction of p21 and p27^*

Christian Fischer, Hugo Sanchez-Ruderisch, Martina Welzel, Bertram Wiedenmann, Toshiyuki Sakai, Sabine André¶, Hans-Joachim Gabius¶1, Levon Khachigian||, Katharina M. Detjen2, and Stefan Rosewicz3

From the Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany, Department of Preventive Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan, ^¶Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, 80539 München, Germany, and the ^||Centre for Vascular Research, The University of New South Wales, The Prince of Wales Hospital, Sydney, New South Wales 2052, Australia

Surface binding of galectin family members has the potential to link distinct glycan structures to growth regulation. Therefore, we addressed the antiproliferative potential of galectin-1 (Gal-1) in a panel of carcinoma cell lines. We discovered growth inhibition by Gal-1 in epithelial tumor cell lines from different origins and provide evidence that this effect requires functional interaction with the 51 integrin. Antiproliferative effects result from inhibition of the Ras-MEK-ERK pathway and consecutive transcriptional induction of p27. We have further identified two Sp1-binding sites in the p27 promoter as crucial for Gal-1 responsiveness. Inhibition of the Ras-MEK-ERK cascade by Gal-1 increased Sp1 transactivation and DNA binding due to reduced threonine phosphorylation of Sp1. Furthermore, Gal-1 induced p21 transcription and selectively increased p27 protein stability. Gal-1-mediated accumulation of p27 and p21 inhibited cyclin-dependent kinase 2 activity and ultimately resulted in G₁ cell cycle arrest and growth inhibition. These data define a novel mechanism whereby Gal-1 regulates epithelial tumor cell homeostasis via carbohydrate-dependent interaction with the 51 integrin.

Received for publication, October 12, 2004 , and in revised form, July 29, 2005.

^* 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 Supported by a grant from the Mizutani Foundation for Glycoscience.

³ Supported by grants from Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Wilhelm-Sander Stiftung, Else Kröner Fresenius Stiftung, Berliner Krebsgesellschaft, and Sonnenfeld-Stiftung.

² Supported by a grant from Wilhelm-Sander Stiftung. To whom correspondence should be addressed: Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Augustenburger Platz 1, D-13353 Berlin, Germany. Tel.: 49-30-450-559-649; Fax: 49-30-450-559-939; E-mail: katharina.detjen{at}charite.de.

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