Subcellular localization and analysis of apparent 180-kDa and 220-k...
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1996 Nov 8;271(45):28630-5.Subcellular localization and analysis of apparent 180-kDa and 220-kDa proteins of the breast cancer susceptibility gene, BRCA1.1, , , , , .1Cancer Research, Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285, USA. Thomas_James_AbstractThe breast cancer susceptibility gene BRCA1 encodes an 1863-amino acid protein that acts as a tumor suppressor. The biochemical function of BRCA1 is unknown, and there are conflicting results describing its subcellular location. We have identified a 220-kDa protein, which is reactive with three antibodies raised against the amino- and carboxyl-terminal regions of BRCA1. Immunoflourescence staining with an antibody to the carboxyl terminus of BRCA1 localized the protein to the nucleus of breast, ovarian, and cervical carcinoma-derived cell lines. A similar result was observed by biochemical subcellular fractionation that indicated that the 220-kDa protein was localized primarily to the nucleus of cell lines established from breast carcinomas. In addition to the 220-kDa protein, one antibody, C-20, also recognized a 180-kDa protein in MDA-MB-468 total cell lysates that was not detected by the other two antibodies. Several observations suggest the 180-kDa protein is the epidermal growth factor (EGF) receptor: (i) C-20 reacted avidly with a 180-kDa protein immunoprecipitated by an antibody to the EGF (ii) an EGF receptor antibody detected a 180-kDa protein immunoprecipitated by C-20; (iii) the affinity purified EGF receptor was both immunoprecipitated and detected on immunoblots by the C-20 antibody but not another BRCA1 (iv) similar phosphopeptide maps were generated from the EGF receptor and the 180-kDa protein immunoprecipitated by C-20, and this peptide map was distinct from the 220-kD and (v) the C-20 immunizing peptide bears sequence identity to the EGF receptor. These results indicate that BRCA1 is a 220-kDa nuclear protein and that the 180-kDa protein reported previously may be unrelated to BRCA1.PMID: 8910495
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DNA Double-Strand Breaks Repair and Signaling of Human Gliomas and Normal Brain Cells in Response to Radiation: Potential Impact of the ATM-and BRCA1- Dependent Pathways
By Adeline Granzotto, Zuzana Bencokova, Guillaume Vogin, Cle?ment Devic, Aure?lie Joubert, Jacques Balosso and Nicolas Foray
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Figure 1. Model for describing the radiation-induced ATM nucleo-shuttlingTable 1.
Figure 2. Number of γ-H2AX foci assessed 24 h after 2 Gy X-rays in the indicated human tumour and normal brain cell lines. Data shown are the mean ± standard error of 3 independent replicates, at least. Dotted cell lines indicated the average corresponding value of γ-H2AX foci for radioresistant skin fibroblasts published elsewhere (Joubert et al., 2008).
Figure 3. Number of pATM foci assessed 10 min after 2 Gy X-rays in the indicated human tumour and normal brain cell lines. Data shown are the mean ± standard error of 3 independent replicates, at least. Dotted cell lines indicated the average corresponding value of pATM foci for radioresistant skin fibroblasts obtained in our lab (Granzotto et al., submitted).
Figure 4. Representative example of anti-BRCA1 immunoblots of nuclear extracts from the indicated human cells exposed to 15 Gy followed by 4 h for repair. Expression of BRCA1 was quantified by grey scale analysis in arbitrary units.
Figure 5. A. Anti-BRCA1 immunofluorescence applied to the indicated cell lines after 15 Gy X-rays followed by 4 h for repair. B. Representative examples of pBRCA1ser1423 signals obtained in U87, GHD and M059J cell lines in the same conditions.
Figure 6. Number of residual γ-H2AX foci per cell as a function of the corresponding number of pATM foci per cell for all the human glioma (closed losanges) and normal brain cells (open squares) described in this report. All the foci data are shown in Fig. 1 and 2 as histogram. Each plot is represented by the mean ± standard error of 3 independent replicates, at least. Blue and pink confidence zones correspond to the values from human primary fibroblasts belonging to the radiosensitivity group I and II, respectively (see Discussion). Green confidence zone corresponds to values from the C6, 9L and F98 rodent glioma cells.
Figure 7. Schematic recapitulation of our observation. Bold expressions represent the first experimental observations.
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ParticipateHighlight: BRCA1 and BRCA2 proteins in breast cancer.
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2002 Oct 1;59(1):68-83.Highlight: BRCA1 and BRCA2 proteins in breast cancer..Mount Sinai School of Medicine, Department of Pathology, New York, New York 10029, USA. dianne.daniel@mssm.eduAbstractHeterozygous carriers of loss-of-function germline mutations in the BRCA1 or BRCA2 breast cancer susceptibility genes have a predisposition to breast and ovarian cancer. Multiple functions have been ascribed to the products of these genes, linking them to pathways that inhibit progression to neoplasia. Various investigators have assigned roles for these tumor suppressor gene products in the cell functions of genome repair, transcription, and growth control. There is emerging evidence that BRCA1 may participate in ubiquitin E3 ligase activity. BRCA1 and BRCA2 have each been implicated in chromatin remodeling dynamics via protein partnering. Ubiquitin ligase and chromatin remodeling activities need not be mutually exclusive and both may function in DNA repair, transcriptional regulation, or cell cycle control. Here we highlight certain recent findings and currently unanswered questions regarding BRCA1 and BRCA2 in breast cancer.Copyright 2002 Wiley-Liss, Inc.PMID:
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2006 Mar 2;25(9):1391-9.BRCA1 and FOXA1 proteins coregulate the expression of the cell cycle-dependent kinase inhibitor p27(Kip1).1, , , , , .1Department of Medicine, Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA. ewilliamson@salud.unm.eduAbstractWe have previously shown that the breast cancer susceptibility gene, BRCA1, can transcriptionally activate the p27(Kip1) promoter. The BRCA1-responsive element was defined as a 35 bp region from position -545 to -511. We next determined that within this region is also a potential binding site for the transcription factor Forkhead box (FOX)A1. RNA and protein analysis as well as immunohistochemistry showed that expression of FOXA1 correlated with the expression of the estrogen receptor in a panel of breast cancer cell lines and tissues. In transient transfection reporter assays, FOXA1 could activate the p27(Kip1) promoter. Cotransfection of BRCA1 and FOXA1 resulted in a synergistic activation of the p27(Kip1) promoter. Mutation of the FOXA1 DNA-binding site in the p27(Kip1) promoter-luciferase construct significantly diminished the activity of FOXA1 alone or in combination with BRCA1. Cotransfection of FOXA1 and BRCA1 resulted in a greater amount of each protein compared to transfection of each expression vector alone. The half-life of FOXA1 was increased when coexpressed with BRCA1. Electrophoretic mobility shift assay analysis demonstrated that FOXA1 could bind to a wild-type oligonucleotide containing the FOXA1 binding site in the p27(Kip1) promoter, but this binding was lost upon mutation of this FOXA1 binding site. The protein-DNA binding complex could be supershifted with an antibody directed against FOXA1. The activity of the p27(Kip1) promoter as well as FOXA1 expression was reduced in cells treated with BRCA1 siRNA, thus silencing the expression of BRCA1 protein. In summary, we identified a FOXA1 binding site within the BRCA1-responsive element of the p27(Kip1) promoter and showed that FOXA1 activated the promoter alone and in conjunction with BRCA1. Furthermore, we identified high expression of FOXA1 in breast cancer cell lines and tissues, discovered a role for BRCA1 in the regulation of p27(Kip1) transcription and a possible interaction with BRCA1.PMID:
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):884-93.Regulation of BRCA1, BRCA2 and BARD1 intracellular trafficking..Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, New South Wales, Australia. beric_henderson@wmi.usyd.edu.auAbstractThe subcellular location and function of many proteins are regulated by nuclear-cytoplasmic shuttling. BRCA1 and BARD1 provide an interesting model system for understanding the influence of protein dimerization on nuclear transport and localization. These proteins function predominantly in the nucleus to regulate cell cycle progression, DNA repair/recombination and gene transcription, and their export to the cytoplasm has been linked to apoptosis. Germ-line mutations in the BRCA1/BRCA2 and BARD1 genes predispose to risk of breast/ovarian cancer, and certain mutations impair protein function and nuclear accumulation. BRCA1 and BARD1 shuttle between the n however heterodimerization masks the nuclear export signals located within each protein, causing nuclear retention of the BRCA1-BARD1 complex and potentially influencing its role in DNA repair, cell survival and regulation of centrosome duplication. This review discusses BRCA1, BRCA2 and BARD1 subcellular localization with emphasis on regulation of transport by protein dimerization and its functional implications.PMID:
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