Visit our Expo - Redox and Inflammation signaling 2012

Session III : Protein kinase cascades as therapeutic targets Poster III, 12
Small GTPases Ras modulate transforming growth factor-beta 1-induced extracellular
matrix síntesis.
Begoña Cenador, Isabel Fuentes-Calvo, Eugenio Santos1, José M. López-Novoa and
Carlos Martínez-Salgado2.
Departamento de Fisiología y Farmacología, Universidad de Salamanca, Avda. Campo
Charro s/n, 37007 Salamanca, 1Centro de Investigación del Cáncer, Campus Miguel de
Unamuno s/n, 37007 Salamanca, and 2Unidad de Investigación, Hospital Universitario
de Salamanca, Paseo San Vicente 58-182, 37007 Salamanca.
Ras proteins are small GTPases with prooncogenic effect that act as transducers of
extracellular signals that regulate cell survival, growth and differentiation. Transforming
growth factor beta 1 (TGF-beta 1) has a relevant role in the origin and maintenance of
glomerulosclerosis (GSC) and tubule-interstitial fibrosis (TIF). TGF-beta and Ras signalling
pathways are close related: TGF-beta 1 overcomes Ras mitogenic effects and Ras counteracts
TGF-beta signalling. TIF is associated to increases in Ras, and with the activation of its
signalling pathways Erk/MAPK (mitogen activated protein kinases) and phosphatidylinositol-
3-kinase (PI3K)/Akt in a renal fibrosis model. We have studied the role of Ras, Erk/MAPK
and Akt in TGF-beta 1 mediated extracellular matrix (ECM) synthesis, using embrionary
fibroblasts from knockout (KO) mice for Sos 1 (sos 1-/-), a guanidine nucleotide exchange
factor that is the main Ras activating protein. Fibronectin and collagen type I expression, as
well as total collagen synthesis, is much bigger in sos 1-/- fibroblasts than in control sos 1+/+
fibroblasts, both in basal conditions and after TGF-beta 1 treatment. Ras activation is higher
in sos 1-/- fibroblasts than in controls. Phosphorylated Akt expression is also bigger in sos 1-/-
fibroblasts than in controls, but there are no differences in phosphorylated Erk expression.
These studies show that Ras may down-regulate TGF-beta 1-induced ECM synthesis, and the
Akt signalling pathway participates in the increase in ECM synthesis in sos 1-/- fibroblasts.
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