Modulation of the TGF{beta}/Smad signaling pathway in mesangial cells by CTGF/CCN2

Journal Article · Fri Jul 15 04:00:00 EDT 2005 · Experimental Cell Research

DOI:https://doi.org/10.1016/j.yexcr.2005.03.022· OSTI ID:20717627

Abdel Wahab, Nadia ^[1]; Weston, Benjamin S ^[1]; Mason, Roger M ^[1]

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1. Cell and Molecular Biology Section, Division of Biomedical Sciences, Imperial College London, Sir Alexander Fleming Building, South Kensington, London, SW7 2AZ (United Kingdom)

Transforming growth factor-beta (TGF{beta}) drives fibrosis in diseases such as diabetic nephropathy (DN). Connective tissue growth factor (CTGF; CCN2) has also been implicated in this, but the molecular mechanism is unknown. We show that CTGF enhances the TGF{beta}/Smad signaling pathway by transcriptional suppression of Smad 7 following rapid and sustained induction of the transcription factor TIEG-1. Smad 7 is a known antagonist of TGF{beta} signaling and TIEG-1 is a known repressor of Smad 7 transcription. CTGF enhanced TGF{beta}-induced phosphorylation and nuclear translocation of Smad 2 and Smad 3 in mesangial cells. Antisense oligonucleotides directed against TIEG-1 prevented CTGF-induced downregulation of Smad 7. CTGF enhanced TGF{beta}-stimulated transcription of the SBE4-Luc reporter gene and this was markedly reduced by TIEG-1 antisense oligonucleotides. Expression of the TGF{beta}-responsive genes PAI-1 and Col III over 48 h was maximally stimulated by TGF{beta} + CTGF compared to TGF{beta} alone, while CTGF alone had no significant effect. TGF{beta}-stimulated expression of these genes was markedly reduced by both CTGF and TIEG-1 antisense oligonucleotides, consistent with the endogenous induction of CTGF by TGF{beta}. We propose that under pathological conditions, where CTGF expression is elevated, CTGF blocks the negative feedback loop provided by Smad 7, allowing continued activation of the TGF{beta} signaling pathway.

• OSTI ID: 20717627
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 2 Vol. 307; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CONNECTIVE TISSUE
DISEASES
FIBROSIS
GENES
GROWTH FACTORS
INHIBITION
OLIGONUCLEOTIDES
PHOSPHORYLATION
TRANSCRIPTION
TRANSCRIPTION FACTORS