BRCA1 regulates the interferon gamma-mediated apoptotic response.
BRCA1 is a tumor suppressor gene implicated in transcriptional regulation. We have generated cell lines with inducible expression of BRCA1 as a tool to identify downstream targets that may be important mediators of BRCA1 function. Oligonucleotide array-based expression profiling identified 11 previously described interferon regulated genes that were up-regulated following inducible expression of BRCA1. Northern blot analysis revealed that a subset of the identified targets including IRF-7, MxA, and ISG-54 were synergistically up-regulated by BRCA1 in the presence of interferon gamma (IFN-gamma) but not interferons alpha or beta. Importantly, IFN-gamma-mediated induction of IRF-7 and MxA was attenuated in the BRCA1 mutant cell line HCC1937, an effect that was rescued following reconstitution of exogenous wild type BRCA1 in these cells. Furthermore, reconstituted BRCA1 sensitized HCC1937 cells to IFN-gamma-induced apoptotic cell death. This study identifies BRCA1 as a component of the IFN-gamma-regulated signaling pathway and suggests that BRCA1 may play a role in the regulation of IFN-gamma-mediated apoptosis.
Andrews
Heather N
HN
Department of Oncology, Cancer Research Centre, The Queen's University Belfast, Belfast BT9 7AB, Northern Ireland.
Mullan
Paul B
PB
McWilliams
Stewart
S
Sebelova
Sarka
S
Quinn
Jennifer E
JE
Gilmore
Paula M
PM
McCabe
Nuala
N
Pace
Amy
A
Koller
Beverly
B
Johnston
Patrick G
PG
Haber
Daniel A
DA
Harkin
D Paul
DP
D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D019204:GTP-Binding Proteins; D005786:Gene Expression Regulation; D019398:Genes, BRCA1 / Q000502:physiology*; D006801:Humans; D050839:Interferon Regulatory Factor-7; D007371:Interferon-gamma / Q000502:physiology*; D064547:Myxovirus Resistance Proteins; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis; D015854:Up-Regulation
D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D007371:Interferon-gamma; D019204:GTP-Binding Proteins