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BARD1 mediates TGF-β signaling in pulmonary fibrosis.

André PA, Prêle CM, Vierkotten S, Carnesecchi S, Donati Y, Chambers RC, Pache JC, Crestani B, Barazzone-Argiroffo C, Königshoff M, Laurent GJ, Irminger-Finger I - Respir. Res. (2015)

Bottom Line: Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-β signaling, both recognized factors driving lung fibrosis.Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1β in fibrotic tissues.Our data suggest that FL BARD1 and BARD1β might be mediators of pleiotropic effects of TGF-β.

View Article: PubMed Central - PubMed

Affiliation: Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland. Pierre-Alain.Andre@unige.ch.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-β signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1β, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis.

Methods: We investigated BARD1 expression as a function of TGF-β in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients.

Results: FL BARD1 and BARD1β were upregulated in response to TGF-β in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1β in fibrotic tissues.

Conclusion: Our data suggest that FL BARD1 and BARD1β might be mediators of pleiotropic effects of TGF-β. In particular BARD1β might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment.

No MeSH data available.


Related in: MedlinePlus

Signaling from TGF-β towards FL BARD1 and BARD1β expression in epithelial cells and fibroblasts might contribute to lung fibrosis
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Fig8: Signaling from TGF-β towards FL BARD1 and BARD1β expression in epithelial cells and fibroblasts might contribute to lung fibrosis

Mentions: Knowing what causes FL BARD1 and BARD1β upregulation in fibrotic tissues may help us resolve whether the particular expression pattern is cause or consequence of the fibrotic transformation of lung tissue. Our data suggest that BARD1 and BARD1β are downstream of TGF-β in exerting effects on epithelial cells and fibroblasts (Fig. 8). Several reports have linked BARD1 expression to TGF-β-dependent pathways [33, 34]. Indeed, of the large number of transcription factors that specifically bind to the BARD1 promoter [45], several are activated in a TGF-β pathway (Additional file 1: Table S1), consistent with our finding that BARD1 expression can be regulated by TGF-β.Fig. 8


BARD1 mediates TGF-β signaling in pulmonary fibrosis.

André PA, Prêle CM, Vierkotten S, Carnesecchi S, Donati Y, Chambers RC, Pache JC, Crestani B, Barazzone-Argiroffo C, Königshoff M, Laurent GJ, Irminger-Finger I - Respir. Res. (2015)

Signaling from TGF-β towards FL BARD1 and BARD1β expression in epithelial cells and fibroblasts might contribute to lung fibrosis
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4587901&req=5

Fig8: Signaling from TGF-β towards FL BARD1 and BARD1β expression in epithelial cells and fibroblasts might contribute to lung fibrosis
Mentions: Knowing what causes FL BARD1 and BARD1β upregulation in fibrotic tissues may help us resolve whether the particular expression pattern is cause or consequence of the fibrotic transformation of lung tissue. Our data suggest that BARD1 and BARD1β are downstream of TGF-β in exerting effects on epithelial cells and fibroblasts (Fig. 8). Several reports have linked BARD1 expression to TGF-β-dependent pathways [33, 34]. Indeed, of the large number of transcription factors that specifically bind to the BARD1 promoter [45], several are activated in a TGF-β pathway (Additional file 1: Table S1), consistent with our finding that BARD1 expression can be regulated by TGF-β.Fig. 8

Bottom Line: Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-β signaling, both recognized factors driving lung fibrosis.Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1β in fibrotic tissues.Our data suggest that FL BARD1 and BARD1β might be mediators of pleiotropic effects of TGF-β.

View Article: PubMed Central - PubMed

Affiliation: Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland. Pierre-Alain.Andre@unige.ch.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-β signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1β, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis.

Methods: We investigated BARD1 expression as a function of TGF-β in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients.

Results: FL BARD1 and BARD1β were upregulated in response to TGF-β in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1β in fibrotic tissues.

Conclusion: Our data suggest that FL BARD1 and BARD1β might be mediators of pleiotropic effects of TGF-β. In particular BARD1β might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment.

No MeSH data available.


Related in: MedlinePlus