The role of BRCA1 in transcriptional regulation and cell cycle control

Mullan, Paul B.; Quinn, Jennifer E.; Harkin, D. Paul

doi:10.1038/sj.onc.1209872

Cited by 274 publications

(242 citation statements)

References 83 publications

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“…BRCA1 is an important regulatory protein. It is involved in the regulation of the cell cycle, DNA damage repair, transcription and chromatin remodeling (Starita and Parvin, 2003;Deng, 2006;Ko et al, 2006;Mullan et al, 2006;Rosen et al, 2006;Yarden and Papa, 2006). Recent evidence revealed a role of BRCA1 in the regulation of numeral homeostasis of centrosomes (Indraccolo et al, 2006;Ouchi, 2006).…”

Section: Introductionmentioning

confidence: 99%

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

et al. 2007

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Metastasis-associated tumor antigen 1 (MTA1), a component of the nucleosome remodeling and deacetylating (NuRD) complex is routinely upregulated in several cancers. In the present study, we investigated the potential role of MTA1 in BRCA1 transcriptional repression and subsequent chromosomal instability. MTA1-NuRD complex was found to negatively regulate BRCA1 transcription by physically associating with an atypical estrogen-responsive element (ERE) on the BRCA1 promoter. Moreover, MTA1 and HDAC complex recruited to the ERE of BRCA1 promoter in an ER a-dependent manner. Accordingly, BRCA1 protein levels were enhanced by silencing of either MTA1 expression or by treatment with the specific histone deacetylase inhibitor trichostatin A. MTA1's strong repressive effects on BRCA1 expression was supported by our observation that cells stably overexpressing MTA1 showed centrosome amplification which has been long implicated as a phenotype for BRCA1 repression. Accordingly, overexpression of BRCA1 in cells stably over expressing MTA1 resulted in restoration of normal centrosome numbers. Together, these findings strongly implicate MTA1 in the transcriptional repression of BRCA1 leading to abnormal centrosome number and chromosomal instability.

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Section: Introductionmentioning

confidence: 99%

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

et al. 2007

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“…BRCA1 is a tumorsuppressor gene that is critical for genomic stability through facilitating DNA repair, chromatin remodeling, cell-cycle arrest and transcriptional regulation (Boulton, 2006;Rosen et al, 2006). BRCA1 can act as either a corepressor or a coactivator of transcription by interacting with numerous transcription factors, such as estrogen receptor (ER)-a, p53, STAT1, c-Myc, CtIP and ZBRK1 (Mullan et al, 2006). Furthermore, the ability of BRCA1 to regulate cell-cycle progression depends on the transcriptional regulation of multiple cell-cycle genes, such as p21/waf1 and p27/kip1 to regulate the G1/S checkpoint, as well as cyclin B1, 14-3-3s, wee1 kinase and GADD45 to influence the G2/M-phase transition (Mullan et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…BRCA1 can act as either a corepressor or a coactivator of transcription by interacting with numerous transcription factors, such as estrogen receptor (ER)-a, p53, STAT1, c-Myc, CtIP and ZBRK1 (Mullan et al, 2006). Furthermore, the ability of BRCA1 to regulate cell-cycle progression depends on the transcriptional regulation of multiple cell-cycle genes, such as p21/waf1 and p27/kip1 to regulate the G1/S checkpoint, as well as cyclin B1, 14-3-3s, wee1 kinase and GADD45 to influence the G2/M-phase transition (Mullan et al, 2006). A recent study indicates that BRCA1 can act as a CTD kinase inhibitor contributing to the activation of p21/waf1 gene expression (Moisan and Gaudreau, 2006), providing another mechanism whereby BRCA1 influences transcription and cell-cycle progression.…”

Section: Introductionmentioning

confidence: 99%

Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells

et al. 2007

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The inheritance of one defective BRCA1 or BRCA2 allele predisposes an individual to developing breast and ovarian cancers. BRCA1 is a multifunctional tumor suppressor protein, which through interaction with a vast array of proteins has implications in processes such as cell cycle, transcription, DNA damage response and chromatin remodeling. Conversely, the oncogene, cyclin D1 is overexpressed in about 35% of all breast cancer cases. In this study, we provide detailed analyses on the phosphorylation state of BRCA1 by cyclin D1/cdk4 complexes. In particular, we have identified Ser 632 of BRCA1 as a cyclin D1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin D1/cdk4 activity resulted in increased BRCA1 DNA binding at particular promoters in vivo. In addition, we identified multiple novel genes that are bound by BRCA1 in vivo. Collectively, these results indicate that cyclin D1/cdk4-mediated phosphorylation of BRCA1 inhibits the ability of BRCA1 to be recruited to particular promoters in vivo. Therefore, cyclin D1/Cdk4 phosphorylation of BRCA1 could provide a mechanism to interfere with the DNA-dependent activities of BRCA1.

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“…BRCA1 encodes a 1,863-amino-acid protein that associates with a multitude of proteins involved in cell cycle checkpoint regulation, DNA repair, transcription, chromatin remodeling, and ubiquitination (9)(10)(11)(12)(13), suggesting that BRCA1 plays a critical role in the cellular response to DNA damage. However, the exact mechanism by which BRCA1 functions in the DNA damage response is not completely understood, partly due to the paucity of human BRCA1-null cell lines available for study.…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of a Novel BRCA1-Null Ovarian Cancer Cell Line in Response to Ionizing Radiation

DelloRusso

Welcsh

Wang

et al. 2007

Molecular Cancer Research

111

110

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The breast and ovarian cancer susceptibility gene BRCA1 plays a major role in the DNA damage response pathway. The lack of well-characterized human BRCA1-null cell lines has limited the investigation of BRCA1 function, particularly with regard to its role in ovarian cancer. We propagated a novel BRCA1-null human ovarian cancer cell line UWB1.289 from a tumor of papillary serous histology, the most common form of ovarian carcinoma. UWB1.289 carries a germline BRCA1 mutation within exon 11 and has a deletion of the wild-type allele. UWB1.289 is estrogen and progesterone receptor negative and has an acquired somatic mutation in p53, similar to the commonly used BRCA1-null breast cancer cell line HCC1937. We used ionizing radiation to induce DNA damage in both UWB1.289 and in a stable UWB1.289 line in which wild-type BRCA1 was restored. We examined several responses to DNA damage in these cell lines, including sensitivity to radiation, cell cycle checkpoint function, and changes in gene expression using microarray analysis. We observed that UWB1.289 is sensitive to ionizing radiation and lacks cell cycle checkpoint functions that are a normal part of the DNA damage response. Restoration of wild-type BRCA1 function in these cells partially restores DNA damage responses. Expression array analysis not only supports this partial functional correction but also reveals interesting new information regarding BRCA1-positive regulation of the expression of claudin 6 and other metastasis-associated genes and negative regulation of multiple IFN-inducible genes. (Mol Cancer Res 2007;5(1):35 -45)

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The role of BRCA1 in transcriptional regulation and cell cycle control

Cited by 274 publications

References 83 publications

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells

Functional Characterization of a Novel BRCA1-Null Ovarian Cancer Cell Line in Response to Ionizing Radiation

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