Abstract 2296: An isoform of BARD1, associated with many types of cancer, is a driver of oncogenesis by inducing telomere aberrations in vitro and in vivo
| Autor: | Maxim Pilyugin, Irmgard Irminger-Finger, Magdalena Ratajska, Pierre-Alain André |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Cancer Research. 75:2296-2296 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2015-2296 |
| Popis: | BARD1 has tumor suppressor functions by binding to BRCA1 and to p53 via RING finger and ankyrin repeats, respectively. The BARD1-BRCA1 heterodimer has E3 ligase activity, and the BARD1-p53 interaction promotes apoptosis. The expression of N-terminally truncated RING-less BARD1 isoforms, however, was correlated with poor prognosis in various cancers. We performed overexpression experiments with various isoforms of BARD1 and found that BARD1δ, lacking RING and ANK regions, induces cell cycle arrest, multipolar mitotic spindles, genomic instability, and telomere aberrations. Co-localization studies and interaction assays in HeLa, MCF7, or HEK 293 cells, using tagged BARD1δ and full length (FL) BARD1, showed that the BRCT domains, present in BARD1δ and FL BARD1, interact with centrosome binding proteins and telomere binding proteins. BARD1δ overexpressing cells showed multipolar spindles and telomere alterations. Similar telomere alterations were observed in cells with reduced expression of FL BARD1 by siRNA. This is consistent with the observed distinct telomeric abnormalities in blood cells of patients with a BARD1 germline mutation that causes translation of a truncated protein lacking the BRCT domains. CRE-inducible BARD1δ transgenic mice showed dose-dependent growth arrest and tumor formation in various organs. These in vitro and in vivo observations suggest that BARD1δ plays a significant role in tumorigenesis by inducing genomic and telomere instability. Citation Format: Maxim Pilyugin, Pierre-Alain Andre, Magdalena Ratajska, Irmgard Irminger-Finger. An isoform of BARD1, associated with many types of cancer, is a driver of oncogenesis by inducing telomere aberrations in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2296. doi:10.1158/1538-7445.AM2015-2296 |
| Databáze: | OpenAIRE |
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