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Oncogenic Ras-Induced Proliferation Requires Autocrine Fibroblast Growth Factor 2 Signaling in Skeletal Muscle Cells

Constitutively activated Ras proteins are associated with a large number of human cancers, including those originating from skeletal muscle tissue. In this study, we show that ectopic expression of oncogenic Ras stimulates proliferation of the MM14 skeletal muscle satellite cell line in the absence...

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Detalles Bibliográficos
Autores principales: Fedorov, Yuri V., Rosenthal, R. Scott, Olwin, Bradley B.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2001
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199216/
https://www.ncbi.nlm.nih.gov/pubmed/11257129
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author Fedorov, Yuri V.
Rosenthal, R. Scott
Olwin, Bradley B.
author_facet Fedorov, Yuri V.
Rosenthal, R. Scott
Olwin, Bradley B.
author_sort Fedorov, Yuri V.
collection PubMed
description Constitutively activated Ras proteins are associated with a large number of human cancers, including those originating from skeletal muscle tissue. In this study, we show that ectopic expression of oncogenic Ras stimulates proliferation of the MM14 skeletal muscle satellite cell line in the absence of exogenously added fibroblast growth factors (FGFs). MM14 cells express FGF-1, -2, -6, and -7 and produce FGF protein, yet they are dependent on exogenously supplied FGFs to both maintain proliferation and repress terminal differentiation. Thus, the FGFs produced by these cells are either inaccessible or inactive, since the endogenous FGFs elicit no detectable biological response. Oncogenic Ras-induced proliferation is abolished by addition of an anti–FGF-2 blocking antibody, suramin, or treatment with either sodium chlorate or heparitinase, demonstrating an autocrine requirement for FGF-2. Oncogenic Ras does not appear to alter cellular export rates of FGF-2, which does not possess an NH(2)-terminal or internal signal peptide. However, oncogenic Ras does appear to be involved in releasing or activating inactive, extracellularly sequestered FGF-2. Surprisingly, inhibiting the autocrine FGF-2 required for proliferation has no effect on oncogenic Ras-mediated repression of muscle-specific gene expression. We conclude that oncogenic Ras-induced proliferation of skeletal muscle cells is mediated via a unique and novel mechanism that is distinct from Ras-induced repression of terminal differentiation and involves activation of extracellularly localized, inactive FGF-2.
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spelling pubmed-21992162008-05-01 Oncogenic Ras-Induced Proliferation Requires Autocrine Fibroblast Growth Factor 2 Signaling in Skeletal Muscle Cells Fedorov, Yuri V. Rosenthal, R. Scott Olwin, Bradley B. J Cell Biol Report Constitutively activated Ras proteins are associated with a large number of human cancers, including those originating from skeletal muscle tissue. In this study, we show that ectopic expression of oncogenic Ras stimulates proliferation of the MM14 skeletal muscle satellite cell line in the absence of exogenously added fibroblast growth factors (FGFs). MM14 cells express FGF-1, -2, -6, and -7 and produce FGF protein, yet they are dependent on exogenously supplied FGFs to both maintain proliferation and repress terminal differentiation. Thus, the FGFs produced by these cells are either inaccessible or inactive, since the endogenous FGFs elicit no detectable biological response. Oncogenic Ras-induced proliferation is abolished by addition of an anti–FGF-2 blocking antibody, suramin, or treatment with either sodium chlorate or heparitinase, demonstrating an autocrine requirement for FGF-2. Oncogenic Ras does not appear to alter cellular export rates of FGF-2, which does not possess an NH(2)-terminal or internal signal peptide. However, oncogenic Ras does appear to be involved in releasing or activating inactive, extracellularly sequestered FGF-2. Surprisingly, inhibiting the autocrine FGF-2 required for proliferation has no effect on oncogenic Ras-mediated repression of muscle-specific gene expression. We conclude that oncogenic Ras-induced proliferation of skeletal muscle cells is mediated via a unique and novel mechanism that is distinct from Ras-induced repression of terminal differentiation and involves activation of extracellularly localized, inactive FGF-2. The Rockefeller University Press 2001-03-19 /pmc/articles/PMC2199216/ /pubmed/11257129 Text en © 2001 The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Report
Fedorov, Yuri V.
Rosenthal, R. Scott
Olwin, Bradley B.
Oncogenic Ras-Induced Proliferation Requires Autocrine Fibroblast Growth Factor 2 Signaling in Skeletal Muscle Cells
title Oncogenic Ras-Induced Proliferation Requires Autocrine Fibroblast Growth Factor 2 Signaling in Skeletal Muscle Cells
title_full Oncogenic Ras-Induced Proliferation Requires Autocrine Fibroblast Growth Factor 2 Signaling in Skeletal Muscle Cells
title_fullStr Oncogenic Ras-Induced Proliferation Requires Autocrine Fibroblast Growth Factor 2 Signaling in Skeletal Muscle Cells
title_full_unstemmed Oncogenic Ras-Induced Proliferation Requires Autocrine Fibroblast Growth Factor 2 Signaling in Skeletal Muscle Cells
title_short Oncogenic Ras-Induced Proliferation Requires Autocrine Fibroblast Growth Factor 2 Signaling in Skeletal Muscle Cells
title_sort oncogenic ras-induced proliferation requires autocrine fibroblast growth factor 2 signaling in skeletal muscle cells
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199216/
https://www.ncbi.nlm.nih.gov/pubmed/11257129
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