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 |
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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. |
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ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/sj.onc.1208698 |