Affordable Access

Publisher Website

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

Authors
Journal
Experimental Cell Research
0014-4827
Publisher
Elsevier
Publication Date
Volume
312
Issue
11
Identifiers
DOI: 10.1016/j.yexcr.2006.03.008
Keywords
  • Fibroblasts
  • Transforming Growth Factor-β1
  • Ras Proteins
  • Proliferation
  • Extracellular Matrix
  • Collagen
  • Fibronectin

Abstract

Abstract Transforming 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.

There are no comments yet on this publication. Be the first to share your thoughts.