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

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

doi:10.1158/1541-7786.mcr-06-0250

Cited by 47 publications

(38 citation statements)

References 42 publications

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“…This method has been described in detail elsewhere (Buckley et al, 2007). Promoter primers were designed for (1) the NDRG1 proximal promoter region (encompassing EGR1 binding site) and (2) a region approximately 1000 bp upstream as a nonspecific ChIP assay control PCR (see Supplemental Material).…”

Section: Chromatin Immunoprecipitationsmentioning

confidence: 99%

T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

et al. 2010

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T-box 2 (TBX2) is a transcription factor involved in mammary development and is known to be overexpressed in a subset of aggressive breast cancers. TBX2 has previously been shown to repress growth control genes such as p14 ARF and p21 WAF1/cip1 . In this study we show that TBX2 drives proliferation in breast cancer cells and this is abrogated after TBX2 small interfering RNA (siRNA) knockdown or after the expression of a dominant-negative TBX2 protein. Using microarray analysis we identified a large cohort of novel TBX2-repressed target genes including the breast tumour suppressor NDRG1 (N-myc downregulated gene 1). We show that TBX2 targets NDRG1 through a previously undescribed mechanism involving the recruitment of early growth response 1 (EGR1). We show EGR1 is required for the ability of TBX2 to repress NDRG1 and drive cell proliferation. We show that TBX2 interacts with EGR1 and that TBX2 requires EGR1 to target the NDRG1 proximal promoter. Abrogation of either TBX2 or EGR1 expression is accompanied by the upregulation of cell senescence and apoptotic markers. NDRG1 can recapitulate these effects when transfected into TBX2-expressing cells. Together, these data identify a novel mechanism for TBX2-driven oncogenesis and highlight the importance of NDRG1 as a growth control gene in breast tissue.

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Section: Chromatin Immunoprecipitationsmentioning

confidence: 99%

T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

et al. 2010

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“…STAT1, an upstream mediator of IFN signalling, plays an important role in DNA damage repair [20]. In addition, BRCA1, a major regulator of HR-based DNA repair, is required for the enhanced expression of type I IFN-related genes after IFN-γ stimulation [21][22][23][24][25]. Furthermore, an IFN-related gene signature was associated with resistance to chemotherapy and radiation therapy in breast cancer [26].…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells

Jian

Viré

et al. 2014

J. Pathol.

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BRCA2 mutations are significantly associated with early onset breast cancer, and the tumour suppressing function of BRCA2 has been attributed to its involvement in homologous recombination [1]-mediated DNA repair. In order to identify additional functions of BRCA2, we generated BRCA2-knockout HCT116 human colorectal carcinoma cells. Using genome-wide microarray analyses, we have discovered a link between the loss of BRCA2 and the up-regulation of a subset of interferon (IFN)-related genes, including APOBEC3F and APOBEC3G. The overexpression of IFN-related genes was confirmed in different human BRCA2 −/− and mouse Brca2 −/− tumour cell lines, and was independent of either senescence or apoptosis. In isogenic wild type BRCA2 cells, we observed over-expression of IFN-related genes after treatment with DNAdamaging agents, and following ionizing radiation. Cells with endogenous DNA damage because of defective BRCA1 or RAD51 also exhibited over-expression of IFN-related genes. Transcriptional activity of the IFN-stimulated response element (ISRE) was increased in BRCA2 The GEO number for microarray analysis is GSE54830. Author contributionsHX designed the study, carried out most experiments and wrote the manuscript. JX made the BRCA2 knockout cell lines in HCT116, performed DNA damage repair experiments on BRCA2 knockout cells and wrote part of the manuscript. EV performed the CHIP experiment and was involved in manuscript writing. SJ analyzed the data. JW carried out microarray analysis. RT and VW carried out experiments. TK, CC and SA were involved in study design.

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“…The potential role of BRCA1 in transcriptional regulation has been revealed by discovering its ability to bind many important transcription factors, including p53, c-Myc, and STAT1 (13)(14)(15). Expression of several target proteins, including p21 WAF1 , cyclin B1, and EGR1, is activated or repressed by the presence of BRCA1.…”

mentioning

confidence: 99%

Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis

Ahmed

Tsai

Lee

2010

Journal of Biological Chemistry

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The high mobility group AT-hook 2 (HMGA2), a DNA architectural protein, is highly regulated during development and plays an important role in tumorigenesis. Indeed, HMGA2 was overexpressed in many different kinds of tumors. However, the mechanisms regulating HMGA2 expression remain elusive. Using microarray analysis, we found that HMGA2, along with a dozen of other genes, was co-repressed by ZBRK1, BRCA1, and CtIP. BRCA1 exerts its transcriptional repression activity through interaction with the transcriptional repressor ZBRK1 in the central domain, and with CtIP in the C-terminal BRCT domain. Here, we show that ZBRK1, BRCA1, and CtIP form a repression complex that coordinately regulates HMGA2 expression via a ZBRK1 recognition site in the HMGA2 promoter. Depletion of any of the proteins in this complex via adenoviral RNA interference in MCF10A mammary epithelial cells activates HMGA2 expression, resulting in increased colony formation in soft agar. Similarly, depletion of ZBRK1, or ectopic overexpression of HMGA2, in MCF10A cells induces abnormal acinar size with increased cell number and inhibits normal acinar formation. Consistently, many BRCA1-deficient mouse breast tumors express higher levels of HMGA2 than BRCA1-proficient tumors. These results suggest that activation of HMGA2 gene expression through derepression of the ZBRK1/ BRCA1/CtIP complex is a significant step in accelerating breast tumorigenesis.The HMGA family consists of four proteins: HMGA1a, HMGA1b, HMGA1c, and HMGA2.2 HMGA1a, -b, and -c are all encoded by the same gene but vary in length due to alternative splicing (1-3), whereas HMGA2 is encoded by a distinctive gene (4). The common structural motifs in this group include an acidic C terminus and three DNA binding domains called A-T hooks, because they bind short (4 Ϯ 6 bp) AT-rich sequences in the minor groove (5-8). HMGA proteins regulate the expression of many genes through architectural remodeling of the chromatin structure and the formation of multiprotein complexes on promoter/enhancer regions. In accordance with their many roles in transcriptional regulation, aberrant expression of HMGA proteins has been observed in a large number of human cancers (reviewed by Farnet et al. (9)). The HMGA2 architectural protein is critical for a variety of cellular processes, including gene transcription, induction of neoplastic transformation, and promotion of metastatic progression (10, 11). Importantly, HMGA2 overexpression in tumors is associated with poor prognosis and metastasis in breast cancer patients (12). Although it is known that transcriptional repression of HMGA2 may prevent mammary tumorigenesis, the mechanisms governing repression remain elusive.The potential role of BRCA1 in transcriptional regulation has been revealed by discovering its ability to bind many important transcription factors, including p53, c-Myc, and STAT1 (13-15). Expression of several target proteins, including p21 WAF1 , cyclin B1, and EGR1, is activated or repressed by the presence of BRCA1. BRCA1 lacks DNA sequence...

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

Cited by 47 publications

References 42 publications

T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

T-box 2 represses NDRG1 through an EGR1-dependent mechanism to drive the proliferation of breast cancer cells

Up-regulation of the interferon-related genes in BRCA2 knockout epithelial cells

Derepression of HMGA2 via Removal of ZBRK1/BRCA1/CtIP Complex Enhances Mammary Tumorigenesis

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