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

Martı́nez-Salgado, Carlos; Fuentes-Calvo, Isabel; Cenador, María Begoña García; Santos, Eugenio; López‐Novoa, José M.

doi:10.1016/j.yexcr.2006.03.008

Cited by 42 publications

(46 citation statements)

References 52 publications

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“…Further analysis of Smadindependent pathways indicated reduced phosphorylation of AKT in AdTGF-β1 treated animals compared to AdTGF-β3. This pathway has been shown to be involved in the fibrotic response in other models (Martinez-Salgado, Fuentes-Calvo, Garcia-Cenador, Santos, & Lopez-Novoa, 2006), and a relative downregulation of AKT might promote fibrotic tissue repair. Similarly, we observed some isoform related differences in the levels of phosphop44/42, which is part of another signalling cascade with cross talk with the Smad pathway (Martinez-Salgado et al, 2006).…”

Section: Discussionmentioning

confidence: 94%

“…This pathway has been shown to be involved in the fibrotic response in other models (Martinez-Salgado, Fuentes-Calvo, Garcia-Cenador, Santos, & Lopez-Novoa, 2006), and a relative downregulation of AKT might promote fibrotic tissue repair. Similarly, we observed some isoform related differences in the levels of phosphop44/42, which is part of another signalling cascade with cross talk with the Smad pathway (Martinez-Salgado et al, 2006). We acknowledge that the differences in induction and phosphorylation of non-Smad signalling proteins are subtle, but the observation nevertheless suggests that TGF-β isoforms 1 and 3 might affect tissue repair in a different manner due to influences on non-Smad signalling pathways and TGF-β receptors.…”

Section: Discussionmentioning

confidence: 94%

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Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3

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Bonniaud

Maaß

et al. 2008

The International Journal of Biochemistry & Cell Biology

154

114

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Tissue repair is a well orchestrated biological process involving numerous soluble mediators, and an imbalance between these factors may result in impaired repair and fibrosis. Transforming growth factor (TGF) β is a key profibrotic element in this process and it is thought that its three isoforms act in a similar way. Here, we report that TGF-β3 administered to rat lungs using transient overexpression initiates profibrotic effects similar to those elicited by TGF-β1, but causes less severe and progressive changes. The data suggest that TGF-β3 does not lead to inhibition of matrix degradation in the same way as TGF-β1, resulting in non-fibrotic tissue repair. Further, TGF-β3 is able to downregulate TGF-β1 induced gene expression, suggesting a regulatory role of TGF-β3. TGF-β3 overexpression results in an upregulation of Smad proteins similar to TGF-β1, but is less efficient in inducing the ALK 5 and TGF-β type II receptor (TβRII). We provide evidence that this difference may contribute to the progressive nature of TGF-β1 induced fibrotic response, in contrast to the limited fibrosis observed following TGF-β3 overexpression. TGF-β3 is important in "normal wound healing", but is outbalanced by TGF-β1 in "fibrotic wound healing" in the lung.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 94%

Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3

Ask

Bonniaud

Maaß

et al. 2008

The International Journal of Biochemistry & Cell Biology

154

114

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“…Western blot analysis was performed as previously described (45). Membranes were incubated with the following antibodies: anti-Akt 1/2 (dilution: 1/1,000), anti-ERK 1 (1/10,000), anti-phospho-ERK (1/2,000), anti-phospho-Akt (1/1,000), anti collagen type I (1/20,000), anti-fibronectin (1/30,000), anti-PCNA (1/5,000), and anti-Ras (1/ 1,000).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Actin and tubulin are affected by TGF-␤1 treatment and therefore were not used as loading controls. Instead we utilized total ERK 1/2 levels as controls for protein loading because their basal levels showed no differences between H-ras ϩ/ϩ and H-ras Ϫ/Ϫ fibroblasts after TGF-␤1 treatment, as we had previously found in H-and N-Ras double-KO fibroblasts (45). Previous results from our laboratory showed that total ERK 1/2 did not change in renal tissue of mice undergoing different manipulations leading to fibrosis and proliferation (61) while tubulin and actin did change.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Our laboratory has shown that the lack of both Hand N-Ras isoforms in fibroblasts downregulates extracellular matrix (ECM) synthesis and mediates proliferation through MEK/ERK activation. TGF-␤1 can upregulate ECM synthesis via phosphatidylinositol-3-kinase (PI3K)/Akt signaling and simultaneously inhibits the ERK pathway (45). However, the effect of H-Ras isoform deficiency has not yet been assessed.…”

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confidence: 99%

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H-Ras isoform modulates extracellular matrix synthesis, proliferation, and migration in fibroblasts

Fuentes-Calvo

Blázquez‐Medela

Eleno

et al. 2012

American Journal of Physiology-Cell Physiology

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Ras GTPases are ubiquitous plasma membrane transducers of extracellular stimuli. In addition to their role as oncogenes, Ras GTPases are key regulators of cell function. Each of the Ras isoforms exhibits specific modulatory activity on different cellular pathways. This has prompted researchers to determine the pathophysiological roles of each isoform. There is a proven relationship between the signaling pathways of transforming growth factor-β1 (TGF-β1) and Ras GTPases. To assess the individual role of H-Ras oncogene in basal and TGF-β1-mediated extracellular matrix (ECM) synthesis, proliferation, and migration in fibroblasts, we analyzed these processes in embryonic fibroblasts obtained from H-Ras knockout mice ( H-ras−/−). We found that H- ras−/− fibroblasts exhibited a higher basal phosphatidylinositol-3-kinase (PI3K)/Akt activation than wild-type (WT) fibroblasts, whereas MEK/ERK 1/2 activation was similar in both types of cells. Fibronectin and collagen synthesis were higher in H -ras−/− fibroblasts and proliferation was lower in H -ras−/− than in WT fibroblasts. Moreover, H-Ras appeared indispensable to maintain normal fibroblast motility, which was highly restricted in H- ras−/− cells. These results suggest that H-Ras (through downregulation of PI3K/Akt activation) could modulate fibroblast activity by reducing ECM synthesis and upregulating both proliferation and migration. TGF-β1 strongly increased ERK and Akt activation in WT but not in H- ras−/− fibroblasts, suggesting that H-Ras is necessary to increase ERK 1/2 activation and to maintain PI3K downregulation in TGF-β1-stimulated fibroblasts. TGF-β1 stimulated ECM synthesis and proliferation, although ECM synthesis was higher and proliferation lower in H- ras−/− than in WT fibroblasts. Hence, H-Ras activation seems to play a key role in the regulation of these effects.

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Amelioration of Systemic Fibrosis in Mice by Angiotensin II Receptor Blockade

Marut

Kavian

Servettaz

et al. 2013

Arthritis & Rheumatism

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Objective. Systemic sclerosis (SSc) is characterized by microvascular damage, fibrosis of skin and visceral organs, and autoimmunity. Previous studies have shown that angiotensin II is involved in the synthesis of type I collagen. We investigated whether the blockade of angiotensin II receptor type I (AT 1 ) by irbesartan reduces skin and lung fibrosis in 2 murine models of SSc. Methods. SSc was induced by daily intradermal injection of HOCl into the backs of BALB/c mice (HOCl-induced SSc). Mice were treated daily with irbesartan by oral gavage.Results. Irbesartan reduced dermal thickness, collagen concentration, Smad2/3, and ␣-smooth muscle actin expression, as well as fibroblast proliferation and H-Ras expression in the skin of mice with HOClinduced SSc. Mice treated with irbesartan also displayed less lung fibrosis, less inflammation, and a lower concentration of collagen in the lungs than untreated mice. Exhaled nitric oxide, inducible nitric oxide synthase, and 3-nitrotyrosine expression in the lungs were decreased following irbesartan treatment. Moreover, irbesartan reduced the number and the proliferation of splenic B and T cells and the serum levels of anti-DNA topoisomerase I autoantibodies.Conclusion. Irbesartan, an AT 1 antagonist, prevents fibrosis and inflammation and inhibits nitric oxide production in HOCl-induced models of systemic fibrosis. Our findings extend the indication of an AT 1 antagonist to SSc patients with diffuse fibrosis, especially those with lung involvement.

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

Cited by 42 publications

References 52 publications

Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3

Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3

H-Ras isoform modulates extracellular matrix synthesis, proliferation, and migration in fibroblasts

Amelioration of Systemic Fibrosis in Mice by Angiotensin II Receptor Blockade

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