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RAGE signaling deficiency in rhabdomyosarcoma cells causes upregulation of PAX7 and uncontrolled proliferation.
J Cell Sci. 2014 Apr 15; 127(Pt 8):1699-711.JC

Abstract

Embryonal rhabdomyosarcomas (ERMSs) show elevated levels of PAX7, a transcription factor that marks quiescent adult muscle stem (satellite) cells and is important for proliferation and survival of activated satellite cells and whose timely repression is required for myogenic differentiation. However, the mechanism of PAX7 accumulation in ERMSs and whether high PAX7 causes uncontrolled proliferation in ERMS remains to be elucidated. The receptor for advanced glycation end-products (RAGE, encoded by AGER) transduces a myogenic and anti-proliferative signal in myoblasts, and stable transfection of the ERMS cell line TE671, which does not express RAGE, with AGER results in reduced proliferation and formation of tumor masses in vivo, and enhanced apoptosis and myogenic differentiation. Herein, we show that RAGE expression is low or absent in human ERMSs. We also show that in ERMS cells (1) PAX7 accumulates owing to absent or low RAGE signaling; (2) elevated PAX7 levels reduce RAGE expression and levels of MyoD and myogenin, muscle-specific transcription factors required for myoblast proliferation arrest and differentiation, respectively; (3) PAX7 supports myoblast proliferation by reducing the levels of MyoD, primarily by promoting its degradation; and (4), when ectopically expressed in ERMS cells, that RAGE upregulates myogenin which upregulates MyoD and downregulates PAX7, with consequent inhibition of proliferation and stimulation of differentiation. Thus, failure to express RAGE and, hence, MyoD and myogenin above a critical level in ERMS cells might result in deregulated PAX7 expression leading to uncontrolled proliferation and, potentially, to rhabdomyosarcomagenesis.

Authors+Show Affiliations

Department of Experimental Medicine, University of Perugia, Perugia 06132, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24554430

Citation

Riuzzi, Francesca, et al. "RAGE Signaling Deficiency in Rhabdomyosarcoma Cells Causes Upregulation of PAX7 and Uncontrolled Proliferation." Journal of Cell Science, vol. 127, no. Pt 8, 2014, pp. 1699-711.
Riuzzi F, Sorci G, Sagheddu R, et al. RAGE signaling deficiency in rhabdomyosarcoma cells causes upregulation of PAX7 and uncontrolled proliferation. J Cell Sci. 2014;127(Pt 8):1699-711.
Riuzzi, F., Sorci, G., Sagheddu, R., Sidoni, A., Alaggio, R., Ninfo, V., & Donato, R. (2014). RAGE signaling deficiency in rhabdomyosarcoma cells causes upregulation of PAX7 and uncontrolled proliferation. Journal of Cell Science, 127(Pt 8), 1699-711. https://doi.org/10.1242/jcs.136259
Riuzzi F, et al. RAGE Signaling Deficiency in Rhabdomyosarcoma Cells Causes Upregulation of PAX7 and Uncontrolled Proliferation. J Cell Sci. 2014 Apr 15;127(Pt 8):1699-711. PubMed PMID: 24554430.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RAGE signaling deficiency in rhabdomyosarcoma cells causes upregulation of PAX7 and uncontrolled proliferation. AU - Riuzzi,Francesca, AU - Sorci,Guglielmo, AU - Sagheddu,Roberta, AU - Sidoni,Angelo, AU - Alaggio,Rita, AU - Ninfo,Vito, AU - Donato,Rosario, Y1 - 2014/02/19/ PY - 2014/2/21/entrez PY - 2014/2/21/pubmed PY - 2014/12/15/medline KW - Embryonal rhabdomyosarcoma KW - MyoD KW - Myogenin KW - PAX7 KW - Proliferation KW - RAGE SP - 1699 EP - 711 JF - Journal of cell science JO - J Cell Sci VL - 127 IS - Pt 8 N2 - Embryonal rhabdomyosarcomas (ERMSs) show elevated levels of PAX7, a transcription factor that marks quiescent adult muscle stem (satellite) cells and is important for proliferation and survival of activated satellite cells and whose timely repression is required for myogenic differentiation. However, the mechanism of PAX7 accumulation in ERMSs and whether high PAX7 causes uncontrolled proliferation in ERMS remains to be elucidated. The receptor for advanced glycation end-products (RAGE, encoded by AGER) transduces a myogenic and anti-proliferative signal in myoblasts, and stable transfection of the ERMS cell line TE671, which does not express RAGE, with AGER results in reduced proliferation and formation of tumor masses in vivo, and enhanced apoptosis and myogenic differentiation. Herein, we show that RAGE expression is low or absent in human ERMSs. We also show that in ERMS cells (1) PAX7 accumulates owing to absent or low RAGE signaling; (2) elevated PAX7 levels reduce RAGE expression and levels of MyoD and myogenin, muscle-specific transcription factors required for myoblast proliferation arrest and differentiation, respectively; (3) PAX7 supports myoblast proliferation by reducing the levels of MyoD, primarily by promoting its degradation; and (4), when ectopically expressed in ERMS cells, that RAGE upregulates myogenin which upregulates MyoD and downregulates PAX7, with consequent inhibition of proliferation and stimulation of differentiation. Thus, failure to express RAGE and, hence, MyoD and myogenin above a critical level in ERMS cells might result in deregulated PAX7 expression leading to uncontrolled proliferation and, potentially, to rhabdomyosarcomagenesis. SN - 1477-9137 UR - https://www.unboundmedicine.com/medline/citation/24554430/RAGE_signaling_deficiency_in_rhabdomyosarcoma_cells_causes_upregulation_of_PAX7_and_uncontrolled_proliferation_ L2 - http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=24554430 DB - PRIME DP - Unbound Medicine ER -