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Andre, Pierre-Alain; Prele, Cecilia M.; Vierkotten, Sarah; Carnesecchi, Stephanie; Donati, Yves; Chambers, Rachel C.; Pache, Jean-Claude; Crestani, Bruno; Barazzone-Argiroffo, Constance; Koenigshoff, Melanie; Laurent, Geoffrey J. and Irminger-Finger, Irmgard (2015): BARD1 mediates TGF-beta signaling in pulmonary fibrosis. In: Respiratory Research 16:118 [PDF, 2MB]

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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-beta signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1 beta, 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-beta in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients. Results: FL BARD1 and BARD1 beta were upregulated in response to TGF-beta 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 BARD1 beta in fibrotic tissues. Conclusion: Our data suggest that FL BARD1 and BARD1 beta might be mediators of pleiotropic effects of TGF-beta. In particular BARD1 beta might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment.

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