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LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor ?1 Expression.

ABSTRACT: Transforming growth factor ?1 (TGF-?1) is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair. Here, we report that four and a half LIM-only protein 2 (FHL2) is a critical regulator of TGF-?1 expression. Devoid of a DNA-binding domain, FHL2 is a transcriptional cofactor that plays the role of coactivator or corepressor, depending on the cell and promoter contexts. We detected association of FHL2 with the TGF-?1 promoter, which showed higher activity in Fhl2^-/- cells than in wild-type (WT) cells in a reporter assay. Overexpression of FHL2 abrogates the activation of the TGF-?1 promoter, whereas the upregulation of TGF-?1 gene transcription correlates with reduced occupancy of FHL2 on the promoter. Moreover, ablation of FHL2 facilitates recruitment of RNA polymerase II on the TGF-?1 promoter, suggesting that FHL2 may be involved in chromatin remodeling in the control of TGF-?1 gene transcription. Enhanced expression of TGF-?1 mRNA and cytokine was evidenced in the livers of Fhl2^-/- mice. We tested the in vivo impact of Fhl2 loss on hepatic fibrogenesis that involves TGF-?1 activation. Fhl2^-/- mice developed more severe fibrosis than their WT counterparts. These results demonstrate the repressive function of FHL2 on TGF-?1 expression and contribute to the understanding of the TGF-?-mediated fibrogenic response.

SUBMITTER: Dahan J

PROVIDER: S-EPMC5477553 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression.

Dahan Jennifer J Levillayer Florence F Xia Tian T Nouët Yann Y Werts Catherine C Fanton d'Andon Martine M Adib-Conquy Minou M Cassard-Doulcier Anne-Marie AM Khanna Varun V Chen Ju J Tordjmann Thierry T Buendia Marie-Annick MA Jouvion Grégory G Wei Yu Y

Molecular and cellular biology 20170502 10

Transforming growth factor β1 (TGF-β1) is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair. Here, we report that four and a half LIM-only protein 2 (FHL2) is a critical regulator of TGF-β1 expression. Devoid of a DNA-binding domain, FHL2 is a transcriptional cofactor that plays the role of coactivator or corepressor, depending on the cell and promoter contexts. We detected association of FHL2 with the TGF-β1 prom ...[more]

PMID: 28223370

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Project description:BACKGROUND:Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor ? (TGF-?) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 & Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-?1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown. METHODS:We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle-specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis. RESULTS:We demonstrate that LMO7 is induced postinjury and by TGF-? in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-? signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-? treatment. TGF-? neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-? signaling by inducing expression of Tgfb1 mRNA, TGF-? protein, ?v and ?3 integrins that promote activation of latent TGF-?, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1-dependent TGF-? autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy. CONCLUSIONS:LMO7 is induced by TGF-? and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-? pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.

Dataset Information

LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor ?1 Expression.

Publications

LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression.

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