The 2,5 oligoadenylate synthetase/RNaseL pathway is a novel effector of BRCA1- and interferon-γ-mediated apoptosis

BRCA1 has been reported to have roles in DNA damage repair, cell cycle checkpoint control, transcriptional regulation and ubiquitination. We have previously demonstrated that BRCA1 is a potent activator of a subset of interferon (IFN)-regulated genes and that BRCA1 synergistically activated a number...

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Veröffentlicht in:Oncogene 2005-08, Vol.24 (35), p.5492-5501
Hauptverfasser: Mullan, Paul B, Hosey, Alison M, Buckley, Niamh E, Quinn, Jennifer E, Kennedy, Richard D, Johnston, Patrick G, Harkin, D Paul
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Sprache:eng
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Zusammenfassung:BRCA1 has been reported to have roles in DNA damage repair, cell cycle checkpoint control, transcriptional regulation and ubiquitination. We have previously demonstrated that BRCA1 is a potent activator of a subset of interferon (IFN)-regulated genes and that BRCA1 synergistically activated a number of these genes in the presence of IFN- γ , but not type I IFNs. Here we report that one of these targets, 2,5 oligoadenylate synthetase (2,5 OAS), is a mediator of BRCA1/IFN- γ -induced apoptosis. We show that the induction of 2,5 OAS in response to IFN- γ is BRCA1 and STAT1 dependent. Consistent with a role as a negative regulator of proliferation, transient transfection of 2,5 OAS into breast cancer cell lines results in decreased colony growth and apoptosis. Furthermore we show that IFN- γ -induced apoptosis is dependent on functional BRCA1 and STAT1 and we demonstrate that IFN- γ -induced apoptosis is dependent on 2,5 OAS induction. 2,5 OAS is the only known upstream regulator of RNaseL, a recently identified hereditary prostate tumour suppressor gene implicated in apoptosis. We propose that BRCA1 may be an upstream regulator of RNaseL, acting in concert with IFN- γ to transcriptionally activate 2,5 OAS, leading to the downstream activation of RNaseL and apoptosis.
ISSN:0950-9232
1476-5594
DOI:10.1038/sj.onc.1208698