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Originally published In Press as doi:10.1074/jbc.M107627200 on December 5, 2001

J. Biol. Chem., Vol. 277, Issue 9, 6888-6897, March 1, 2002
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Receptor for Advanced Glycation End Products Plays a More Important Role in Cellular Survival than in Neurite Outgrowth during Retinoic Acid-induced Differentiation of Neuroblastoma Cells*

Gangadharan SajithlalDagger , Henri Huttunen§, Heikki Rauvala§, and Gerald MünchDagger

From the Dagger  Department of Neuroimmunological Cell Biology, Interdisziplinäres Zentrum für Klinische Forschung, University of Leipzig, Leipzig 04103, Germany and the § Programme of Molecular Neurobiology, Institute of Biotechnology, and the Department of Biosciences, University of Helsinki, Helsinki FIN-00014, Finland

The receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, is known to interact with amphoterin. This interaction has been proposed to play a role in neurite outgrowth and process elongation during neurodifferentiation. However, there is as yet no direct evidence of the relevance of this pathway to neurodifferentiation under physiological conditions. In this study we have investigated a possible role of RAGE and amphoterin in the retinoic acid-induced differentiation of neuroblastoma cells. The functional inactivation of RAGE by dominant negative and antisense strategies showed that RAGE is not required for process outgrowth or differentiation, although overexpression of RAGE accelerates the elongation of neuritic processes. Using the antisense strategy, amphoterin was shown to be essential for process outgrowth and differentiation, suggesting that amphoterin may interact with other molecules to exert its effect in this context. Interestingly, the survival of the neuroblastoma cells treated with retinoic acid was partly dependent on the expression of RAGE, and inhibition of RAGE function partially blocked the increase in anti-apoptotic protein Bcl-2 following retinoic acid treatment. Based on these results we propose that a combination therapy using RAGE blockers and retinoic acid may prove as a useful approach for chemotherapy for the treatment of neuroblastoma.


* This work was supported by the Bundesministerium für Bildung, Forschung und Technologie, Interdisziplinäres Zentrum für Klinische Forschung (IZKF), at the University of Leipzig (01KS9504, Project N1) and by the Alexander von Humboldt Foundation (to G. S.).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.

To whom correspondence should be addressed: Neuroimmunologische Zellbiologie, IZKF, Leipzig Johannisallee 30a, Leipzig 04103, Germany. Tel.: 49-341-97-15945; Fax: 49-341-97-15949; E-mail: mueg@medizin.uni-leipzig.de.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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