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P035 BARD1 and BARD1 isoforms mediate TGF-β signaling to proliferation and telomere aberations in lung fibrosis

Irminger-Finger, I., Andre, P-A, Ratajska, M., Prêle, C. and Konigshoff, M. (2016) P035 BARD1 and BARD1 isoforms mediate TGF-β signaling to proliferation and telomere aberations in lung fibrosis. QJM: An International Journal of Medicine .

Free to read: https://doi.org/10.1093/qjmed/hcw124.007
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Abstract

Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer, suggesting that molecular pathways regulating proliferation might be deranged in both diseases. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. We have shown that expression of BARD1, a tumor suppressor acting with the breast cancer gene product BRCA1, is upregulated in response to hypoxia and TGF-β signaling, both recognized factors driving lung fibrosis. Interestingly, BARD1 isoforms lacking domains required for tumor suppressor functions, in particular BARD1β, are oncogenic drivers of proliferation in cancers of various origins. 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. We demonstrate that wild type BARD1 and isoform BARD1β also play a role in lung fibrosis as inducers of epithelial cell apoptosis and fibroblast proliferation, respectively. Another isoform of BARD1 affects telomere structures. As changes in telomere length and mutations in the telomerase gene are associated with lung fibrosis, we investigated the correlation of BARD1 or BARD1δ isoform expression on telomere length in human and mouse samples of fibrotic lung tissues. Our data suggest that FL BARD1 and BARD1 isoforms might be mediators of pleiotropic effects of TGF-β on proliferation and telomere structure. In particular BARD1β might be a driver of proliferation and BARD1δ might induce telomeric instability in pulmonary fibrosis and both represent novel targets for treatment.

Item Type: Journal Article
Publisher: Oxford University Press on behalf of the Association of Physicians
Copyright: © 2016 The Authors.
URI: http://researchrepository.murdoch.edu.au/id/eprint/64331
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