The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis
| Autor: | Hannah V, Woodcock, Jessica D, Eley, Delphine, Guillotin, Manuela, Platé, Carmel B, Nanthakumar, Matteo, Martufi, Simon, Peace, Gerard, Joberty, Daniel, Poeckel, Robert B, Good, Adam R, Taylor, Nico, Zinn, Matthew, Redding, Ellen J, Forty, Robert E, Hynds, Charles, Swanton, Morten, Karsdal, Toby M, Maher, Andrew, Fisher, Giovanna, Bergamini, Richard P, Marshall, Andy D, Blanchard, Paul F, Mercer, Rachel C, Chambers |
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| Rok vydání: | 2019 |
| Předmět: |
Science
Cell Cycle Proteins Mechanistic Target of Rapamycin Complex 1 Article Cell Line Transforming Growth Factor beta1 Phosphatidylinositol 3-Kinases Signalling & Oncogenes Ecology Evolution & Ethology MD Multidisciplinary Humans lcsh:Science Adaptor Proteins Signal Transducing Computational & Systems Biology Sirolimus Chemical Biology & High Throughput Human Biology & Physiology TOR Serine-Threonine Kinases Genome Integrity & Repair Fibroblasts respiratory system Tumour Biology Phosphoproteins Idiopathic Pulmonary Fibrosis respiratory tract diseases lcsh:Q Collagen biological phenomena cell phenomena and immunity Genetics & Genomics Signal Transduction |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-16 (2019) Nature Communications |
| DOI: | 10.25418/crick.11410074.v1 |
| Popis: | 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-β1 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. The PI3K/Akt/mTOR pathway has been previously implicated in fibrosis and a pan-PI3K/mTOR inhibitor is currently under clinical evaluation for the treatment of IPF. Here the authors show that the mTORC1/4E-BP1 axis is critical for TGF-β1-induced fibrogenesis in in vitro and ex vivo models and that canonical PI3K/Akt signalling is dispensable. |
| Databáze: | OpenAIRE |
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