BRCA1 Regulates IFN-γ Signaling through a Mechanism Involving the Type I IFNs

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

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)261-270
Number of pages10
JournalMolecular Cancer Research
Volume5
Issue number3
DOIs
Publication statusPublished - Mar 2007

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

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