BRCA1 regulates IFN-gamma signaling through a mechanism involving the type I IFNs.
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.
Buckley
Niamh E
NE
Department of Oncology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.
Hosey
Alison M
AM
Gorski
Julia J
JJ
Purcell
James W
JW
Mulligan
Jude M
JM
Harkin
D Paul
DP
Mullan
Paul B
PB
D017209:Apoptosis; D019313:BRCA1 Protein / Q000032:analysis / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics*; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation
D019313:BRCA1 Protein; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D007371:Interferon-gamma