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The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis.
Woodcock, Hannah V; Eley, Jessica D; Guillotin, Delphine; Platé, Manuela; Nanthakumar, Carmel B; Martufi, Matteo; Peace, Simon; Joberty, Gerard; Poeckel, Daniel; Good, Robert B; Taylor, Adam R; Zinn, Nico; Redding, Matthew; Forty, Ellen J; Hynds, Robert E; Swanton, Charles; Karsdal, Morten; Maher, Toby M; Fisher, Andrew; Bergamini, Giovanna; Marshall, Richard P; Blanchard, Andy D; Mercer, Paul F; Chambers, Rachel C.
Afiliación
  • Woodcock HV; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Building, University College London, London, WC1E 6JF, UK.
  • Eley JD; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Building, University College London, London, WC1E 6JF, UK.
  • Guillotin D; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Building, University College London, London, WC1E 6JF, UK.
  • Platé M; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Building, University College London, London, WC1E 6JF, UK.
  • Nanthakumar CB; Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
  • Martufi M; Target Sciences, Medicines Research Centre, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
  • Peace S; Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
  • Joberty G; Cellzome, a GSK Company, Meyershofstrasse 1, 69117, Heidelberg, Germany.
  • Poeckel D; Cellzome, a GSK Company, Meyershofstrasse 1, 69117, Heidelberg, Germany.
  • Good RB; Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
  • Taylor AR; Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
  • Zinn N; Cellzome, a GSK Company, Meyershofstrasse 1, 69117, Heidelberg, Germany.
  • Redding M; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Building, University College London, London, WC1E 6JF, UK.
  • Forty EJ; Centre for Inflammation and Tissue Repair, UCL Respiratory, Rayne Building, University College London, London, WC1E 6JF, UK.
  • Hynds RE; CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, London, WC1E 6DD, UK.
  • Swanton C; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
  • Karsdal M; CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, London, WC1E 6DD, UK.
  • Maher TM; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
  • Fisher A; Nordic Bioscience, Herlev, 2730, Denmark.
  • Bergamini G; Fibrosis Research Group, Inflammation, Repair & Development Section, NHLI, Imperial College, London, SW3 6LY, UK.
  • Marshall RP; Newcastle Fibrosis Research Group, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK.
  • Blanchard AD; Cellzome, a GSK Company, Meyershofstrasse 1, 69117, Heidelberg, Germany.
  • Mercer PF; Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
  • Chambers RC; Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
Nat Commun ; 10(1): 6, 2019 01 02.
Article en En | MEDLINE | ID: mdl-30602778
Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluation in IPF. Here we demonstrate that rapamycin-insensitive mTORC1 signaling via 4E-BP1 is a critical pathway for TGF-ß1 stimulated collagen synthesis in human lung fibroblasts, whereas canonical PI3K/Akt signaling is not required. The importance of mTORC1 signaling was confirmed by CRISPR-Cas9 gene editing in normal and IPF fibroblasts, as well as in lung cancer-associated fibroblasts, dermal fibroblasts and hepatic stellate cells. The inhibitory effect of ATP-competitive mTOR inhibition extended to other matrisome proteins implicated in the development of fibrosis and human disease relevance was demonstrated in live precision-cut IPF lung slices. Our data demonstrate that the mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfoproteínas / Colágeno / Proteínas Adaptadoras Transductoras de Señales / Factor de Crecimiento Transformador beta1 / Fibroblastos / Diana Mecanicista del Complejo 1 de la Rapamicina Tipo de estudio: Etiology_studies / Guideline Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfoproteínas / Colágeno / Proteínas Adaptadoras Transductoras de Señales / Factor de Crecimiento Transformador beta1 / Fibroblastos / Diana Mecanicista del Complejo 1 de la Rapamicina Tipo de estudio: Etiology_studies / Guideline Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2019 Tipo del documento: Article Pais de publicación: Reino Unido