RAGE (receptor for advanced glycation end products) is a cell surface receptor of the immunoglobulin superfamily whose expression in myofibers is developmentally regulated (Mol Cell Biol 24 (2004) 4880-4894). RAGE, activated by its ligand, HMGB1, transduces an anti-proliferative and promyogenic signal via p38 MAPK activation and p38 MAPK-dependent inhibition of ERK1/2 and JNK: overexpression of RAGE in myoblasts and rhabdomyosarcoma (RMS) cells results in increased myogenic potential and reduced proliferation, migration, invasiveness and tumor formation in vivo, whereas its functional inactivation results in the opposite (Mol Cell Biol 24 (2004) 4880-4894; J Biol Chem 281 (2006) 8242-8253; Am J Pathol, DOI:10.2353/ajpath.2007.070049). Satellite cells in situ and quiescent primary myoblasts do not express RAGE; however, RAGE is rapidly expressed in activated myoblasts in differentiation medium, and its expression is inversely related to the expression of Pax7, a marker of quiescent and proliferating myoblasts/satellite cells. The embryonal variant of RMSs (ERMS) has been proposed to originate from satellite cells and typically expresses low levels of myogenin and high levels of Pax7, and upregulated Pax7 has been suggested to contribute significantly to ERMS genesis. We observed a direct relationship between RAGE and myogenin expression and an inverse relationship between RAGE and Pax7 expression in a panel of human ERMSs. Also, either the blockade of RAGE activity or inactivation of p38 MAPK results in upregulation of Pax7 expression in differentiating myoblasts, suggesting that RAGE might participate in repression of Pax7 expression via p38 MAPK. Consistently, RAGE signaling in RMS cells upregulates myogenin expression via p38 MAPK and causes myogenin-dependent repression of Pax7 expression as investigated by chromatin immunoprecipitation. Our data suggest that RAGE has a role in repression of Pax7 expression, a prerequisite for satellite cell differentiation, and that repression of RAGE expression or function in satellite cells might contribute to Pax7-dependent rhabdomyosarcomagenesis.

RAGE signaling in myoblasts and rhabdomyosarcoma cells causes downregulation of Pax7 expression via p38 MAPK activation and upregulation of myogenin expression

RIUZZI, Francesca;SORCI, Guglielmo;SIDONI, Angelo;DONATO, Rosario Francesco
2007

Abstract

RAGE (receptor for advanced glycation end products) is a cell surface receptor of the immunoglobulin superfamily whose expression in myofibers is developmentally regulated (Mol Cell Biol 24 (2004) 4880-4894). RAGE, activated by its ligand, HMGB1, transduces an anti-proliferative and promyogenic signal via p38 MAPK activation and p38 MAPK-dependent inhibition of ERK1/2 and JNK: overexpression of RAGE in myoblasts and rhabdomyosarcoma (RMS) cells results in increased myogenic potential and reduced proliferation, migration, invasiveness and tumor formation in vivo, whereas its functional inactivation results in the opposite (Mol Cell Biol 24 (2004) 4880-4894; J Biol Chem 281 (2006) 8242-8253; Am J Pathol, DOI:10.2353/ajpath.2007.070049). Satellite cells in situ and quiescent primary myoblasts do not express RAGE; however, RAGE is rapidly expressed in activated myoblasts in differentiation medium, and its expression is inversely related to the expression of Pax7, a marker of quiescent and proliferating myoblasts/satellite cells. The embryonal variant of RMSs (ERMS) has been proposed to originate from satellite cells and typically expresses low levels of myogenin and high levels of Pax7, and upregulated Pax7 has been suggested to contribute significantly to ERMS genesis. We observed a direct relationship between RAGE and myogenin expression and an inverse relationship between RAGE and Pax7 expression in a panel of human ERMSs. Also, either the blockade of RAGE activity or inactivation of p38 MAPK results in upregulation of Pax7 expression in differentiating myoblasts, suggesting that RAGE might participate in repression of Pax7 expression via p38 MAPK. Consistently, RAGE signaling in RMS cells upregulates myogenin expression via p38 MAPK and causes myogenin-dependent repression of Pax7 expression as investigated by chromatin immunoprecipitation. Our data suggest that RAGE has a role in repression of Pax7 expression, a prerequisite for satellite cell differentiation, and that repression of RAGE expression or function in satellite cells might contribute to Pax7-dependent rhabdomyosarcomagenesis.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11391/31891
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