Absence of K-Ras Reduces Proliferation and Migration But Increases Extracellular Matrix Synthesis in Fibroblasts
Autor: | José M, Muñoz-Félix, Isabel, Fuentes-Calvo, Cristina, Cuesta, Nélida, Eleno, Piero, Crespo, José M, López-Novoa, Carlos, Martínez-Salgado |
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Rok vydání: | 2015 |
Předmět: |
Mice
Knockout Extracellular Matrix Proteins Fibroblasts Extracellular Matrix Fibronectins Proto-Oncogene Proteins p21(ras) Transforming Growth Factor beta1 Mice Phosphatidylinositol 3-Kinases Cell Movement Nitriles Butadienes Animals Phosphorylation Cells Cultured Cell Proliferation Signal Transduction |
Zdroj: | Journal of cellular physiology. 231(10) |
ISSN: | 1097-4652 |
Popis: | The involvement of Ras-GTPases in the development of renal fibrosis has been addressed in the last decade. We have previously shown that H- and N-Ras isoforms participate in the regulation of fibrosis. Herein, we assessed the role of K-Ras in cellular processes involved in the development of fibrosis: proliferation, migration, and extracellular matrix (ECM) proteins synthesis. K-Ras knockout (KO) mouse embryonic fibroblasts (K-ras(-/-) ) stimulated with transforming growth factor-β1 (TGF-β1) exhibited reduced proliferation and impaired mobility than wild-type fibroblasts. Moreover, an increase on ECM production was observed in K-Ras KO fibroblasts in basal conditions. The absence of K-Ras was accompanied by reduced Ras activation and ERK phosphorylation, and increased AKT phosphorylation, but no differences were observed in TGF-β1-induced Smad signaling. The MEK inhibitor U0126 decreased cell proliferation independently of the presence of K-ras but reduced migration and ECM proteins expression only in wild-type fibroblasts, while the PI3K-AKT inhibitor LY294002 decreased cell proliferation, migration, and ECM synthesis in both types of fibroblasts. Thus, our data unveil that K-Ras and its downstream effector pathways distinctively regulate key biological processes in the development of fibrosis. Moreover, we show that K-Ras may be a crucial mediator in TGF-β1-mediated effects in this cell type. J. Cell. Physiol. 231: 2224-2235, 2016. © 2016 Wiley Periodicals, Inc. |
Databáze: | OpenAIRE |
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