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J. Biol. Chem., Vol. 281, Issue 12, 8242-8253, March 24, 2006

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The Amphoterin (HMGB1)/Receptor for Advanced Glycation End Products (RAGE) Pair Modulates Myoblast Proliferation, Apoptosis, Adhesiveness, Migration, and Invasiveness

FUNCTIONAL INACTIVATION OF RAGE IN L6 MYOBLASTS RESULTS IN TUMOR FORMATION IN VIVO^*

Francesca Riuzzi¹, Guglielmo Sorci¹, and Rosario Donato²

From the Department of Experimental Medicine and Biochemical Sciences and Istituto Interuniversitario di Miologia, University of Perugia, Casella Postale 81 Succursale 3, 06122 Perugia, Italy

We reported that RAGE (receptor for advanced glycation end products), a multiligand receptor of the immunoglobulin superfamily expressed in myoblasts, when activated by its ligand amphoterin (HMGB1), stimulates rat L6 myoblast differentiation via a Cdc42-Rac-MKK6-p38 mitogen-activated protein kinase pathway, and that RAGE expression in skeletal muscle tissue is developmentally regulated. We show here that inhibition of RAGE function via overexpression of a signaling deficient RAGE mutant (RAGEcyto) results in increased myoblast proliferation, migration, and invasiveness, and decreased apoptosis and adhesiveness, whereas myoblasts overexpressing RAGE behave the opposite, compared with mocktransfected myoblasts. These effects are accompanied by a decreased induction of the proliferation inhibitor, p21^Waf1, and increased induction of cyclin D1 and extent of Rb, ERK1/2, and JNK phosphorylation in L6/RAGEcyto myoblasts, the opposite occurring in L6/RAGE myoblasts. Neutralization of culture medium amphoterin negates effects of RAGE activation, suggesting that amphoterin is the RAGE ligand involved in RAGE-dependent effects in myoblasts. Finally, mice injected with L6/RAGEcyto myoblasts develop tumors as opposed to mice injected with L6/RAGE or L6/mock myoblasts that do not. Thus, the amphoterin/RAGE pair stimulates myoblast differentiation by the combined effect of stimulation of differentiation and inhibition of proliferation, and deregulation of RAGE expression in myoblasts might contribute to their neoplastic transformation.

Received for publication, August 26, 2005 , and in revised form, January 4, 2006.

^* This work was supported by the Ministero dell'Istruzione, dell'Università e della Ricerca-University of Perugia (PRIN 2004, 2004054293), Fondazione Cassa di Risparmio di Perugia Project 2004.0282.020_001, and the Associazione Italiana per la Ricerca contro il Cancro (AIRC 1110) (to R. D.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Section of Anatomy, University of Perugia, Via del Giochetto C.P. 81 Succ. 3, 06122 Perugia, Italy. Tel.: 39-075-585-7453 or 7448; Fax: 39-075-585-7451; E-mail: donato{at}unipg.it.

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