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Involvement of H- and N-Ras isoforms in transforming growth factor-β1-induced proliferation and in collagen and fibronectin synthesis

AuthorsMartínez-Salgado, Carlos; Fuentes-Calvo, Isabel; García-Cenador, Begoña; Santos de Dios, Eugenio ; López-Novoa, José M.
Issue Date2006
CitationExperimental Cell Research 312(11): 2093-2106 (2006)
AbstractTransforming growth factor β1 (TGF-β1) has a relevant role in the origin and maintenance of glomerulosclerosis and tubule-interstitial fibrosis. TGF-β and Ras signaling pathways are closely related: TGF-β1 overcomes Ras mitogenic effects and Ras counteracts TGF-β signaling. Tubule-interstitial fibrosis is associated to increases in Ras, Erk, and Akt activation in a renal fibrosis model. We study the role of N- and H-Ras isoforms, and the involvement of the Ras effectors Erk and Akt, in TGF-β1-mediated extracellular matrix (ECM) synthesis and proliferation, using embrionary fibroblasts from double knockout (KO) mice for H- and N-Ras (H-ras-/-/N-ras-/-) isoforms and from heterozygote mice (H-ras+/-/N-ras+/-). ECM synthesis is increased in basal conditions in H-ras-/-/N-ras-/- fibroblasts, this increase being higher after stimulation with TGF-β1. TGF-β1-induced fibroblast proliferation is smaller in H-ras-/-/N-ras-/- than in H-ras+/-/N-ras+/- fibroblasts. Erk activation is decreased in H-ras-/-/N-ras-/- fibroblasts; inhibition of Erk activation reduces fibroblast proliferation. Akt activation is higher in double KO fibroblasts than in heterozygotes; inhibition of Akt activation also inhibits ECM synthesis. We suggest that H- and N-Ras isoforms downregulate ECM synthesis, and mediate proliferation, in part through MEK/Erk activation. PI3K-Akt pathway activation may be involved in the increase in ECM synthesis observed in the absence of H- and N-Ras.
Identifiersdoi: 10.1016/j.yexcr.2006.03.008
issn: 0014-4827
Appears in Collections:(IBMCC) Artículos
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