The 2,5 oligoadenylate synthetase/RNaseL pathway is a novel effector of BRCA1- and interferon-gamma-mediated apoptosis.
BRCA1 has been reported to have roles in DNA damage repair, cell cycle checkpoint control, transcriptional regulation and ubiquitination. We have previously demonstrated that BRCA1 is a potent activator of a subset of interferon (IFN)-regulated genes and that BRCA1 synergistically activated a number of these genes in the presence of IFN-gamma, but not type I IFNs. Here we report that one of these targets, 2,5 oligoadenylate synthetase (2,5 OAS), is a mediator of BRCA1/IFN-gamma-induced apoptosis. We show that the induction of 2,5 OAS in response to IFN-gamma is BRCA1 and STAT1 dependent. Consistent with a role as a negative regulator of proliferation, transient transfection of 2,5 OAS into breast cancer cell lines results in decreased colony growth and apoptosis. Furthermore we show that IFN-gamma-induced apoptosis is dependent on functional BRCA1 and STAT1 and we demonstrate that IFN-gamma-induced apoptosis is dependent on 2,5 OAS induction. 2,5 OAS is the only known upstream regulator of RNaseL, a recently identified hereditary prostate tumour suppressor gene implicated in apoptosis. We propose that BRCA1 may be an upstream regulator of RNaseL, acting in concert with IFN-gamma to transcriptionally activate 2,5 OAS, leading to the downstream activation of RNaseL and apoptosis.
Mullan
Paul B
PB
Centre for Cancer Research and Cell Biology, Queen's University Belfast, University Floor, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK.
Hosey
Alison M
AM
Buckley
Niamh E
NE
Quinn
Jennifer E
JE
Kennedy
Richard D
RD
Johnston
Patrick G
PG
Harkin
D Paul
DP
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D019313:BRCA1 Protein / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection
D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma; D015088:2',5'-Oligoadenylate Synthetase