Molecular Cancer Research
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Molecular Cancer Research 5, 261-270, March 1, 2007. doi: 10.1158/1541-7786.MCR-06-0250
© 2007 American Association for Cancer Research
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Signaling and Regulation

BRCA1 Regulates IFN-{gamma} Signaling through a Mechanism Involving the Type I IFNs

Niamh E. Buckley, Alison M. Hosey, Julia J. Gorski, James W. Purcell, Jude M. Mulligan, D. Paul Harkin and Paul B. Mullan

Department of Oncology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom

Requests for reprints: Paul B. Mullan, Department of Oncology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, University Floor, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, United Kingdom. Phone: 44-28-9026-3911; Fax: 44-28-9026-3744. E-mail: p.mullan{at}qub.ac.uk

BRCA1 encodes a tumor suppressor gene that is mutated in the germ line of women with a genetic predisposition to breast and ovarian cancer. BRCA1 has been implicated in a number of important cellular functions including DNA damage repair, transcriptional regulation, cell cycle control, and ubiquitination. Using an Affymetrix U95A microarray, IRF-7 was identified as a BRCA1 transcriptional target and was also shown to be synergistically up-regulated by BRCA1 specifically in the presence of IFN-{gamma}, coincident with the synergistic induction of apoptosis. We show that BRCA1, signal transducer and activator of transcription (STAT)-1, and STAT2 are all required for the induction of IRF-7 following stimulation with IFN-{gamma}. We also show that the induction of IRF-7 by BRCA1 and IFN-{gamma} is dependent on the type I IFNs, IFN-{alpha} and IFN-ß. We show that BRCA1 is required for the up-regulation of STAT1, STAT2, and the type I IFNs in response to IFN-{gamma}. We show that BRCA1 is localized at the promoters of the molecules involved in type I IFN signaling leading to their up-regulation. Blocking this intermediary type I IFN step using specific antisera shows the requirement for IFN-{alpha} and IFN-ß in the induction of IRF-7 and apoptosis. Finally, we outline a mechanism for the BRCA1/IFN-{gamma} regulation of target genes involved in the innate immune response, which is dependent on type I IFN signaling. (Mol Cancer Res 2007;5(3):261–70)




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