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. 2007 Mar;5(3):261-70.
doi: 10.1158/1541-7786.MCR-06-0250.

BRCA1 regulates IFN-gamma signaling through a mechanism involving the type I IFNs

Niamh E Buckley  1 , Alison M Hosey, Julia J Gorski, James W Purcell, Jude M Mulligan, D Paul Harkin, Paul B Mullan
Affiliations
Free article

BRCA1 regulates IFN-gamma signaling through a mechanism involving the type I IFNs

Niamh E Buckley et al. Mol Cancer Res. 2007 Mar.
Free article

Abstract

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-beta. 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-beta 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.

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