title: Mitochondrial localization, ELK-1 transcriptional regulation and growth inhibitory functions of BRCA1, BRCA1a, and BRCA1b proteins.
abstract: BRCA1 is a tumor suppressor gene that is mutated in families with breast and ovarian cancer. Several BRCA1 splice variants are found in different tissues, but their subcellular localization and functions are poorly understood at the moment. We previously described BRCA1 splice variant BRCA1a to induce apoptosis and function as a tumor suppressor of triple negative breast, ovarian and prostate cancers. In this study we have analyzed the function of BRCA1 isoforms (BRCA1a and BRCA1b) and compared them to the wild-type BRCA1 protein using several criteria like studying expression in normal and tumor cells by RNase protection assays, subcellular localization/fractionation by immunofluorescence microscopy and Western blot analysis, transcription regulation of biological relevant proteins and growth suppression in breast cancer cells. We are demonstrating for the first time that ectopically expressed GFP-tagged BRCA1, BRCA1a, and BRCA1b proteins are localized to the mitochondria, repress ELK-1 transcriptional activity and possess antiproliferative activity on breast cancer cells. These results suggest that the exon 9, 10, and 11 sequences (aa 263-1365) which contain two nuclear localization signals, p53, Rb, c-Myc, gamma-tubulin, Stat, Rad51, Rad50 binding domains, angiopoietin-1 repression domain are not absolutely required for mitochondrial localization and growth suppressor function of these proteins. Since mitochondrial dysfunction is a hallmark of cancer, we can speculate that the mitochondrial localization of BRCA1 proteins may be functionally significant in regulating both the mitochondrial DNA damage as well as apoptotic activity of BRCA1 proteins and mislocalization causes cancer. J. Cell. Physiol. 219: 634-641, 2009. (c) 2009 Wiley-Liss, Inc.
authors.affiliation: Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Atlanta, Georgia, USA.
authors.forename: Anna W
authors.initials: AW
authors.lastname: Maniccia
authors.forename: Catherine
authors.initials: C
authors.lastname: Lewis
authors.forename: Nurjahan
authors.initials: N
authors.lastname: Begum
authors.forename: Jingyao
authors.initials: J
authors.lastname: Xu
authors.forename: Jianqi
authors.initials: J
authors.lastname: Cui
authors.forename: Galina
authors.initials: G
authors.lastname: Chipitsyna
authors.forename: Kartik
authors.initials: K
authors.lastname: Aysola
authors.forename: Vaishali
authors.initials: V
authors.lastname: Reddy
authors.forename: Ganapathy
authors.initials: G
authors.lastname: Bhat
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Beric
authors.initials: B
authors.lastname: Henderson
authors.forename: E Shyam P
authors.initials: ES
authors.lastname: Reddy
authors.forename: Veena N
authors.initials: VN
authors.lastname: Rao
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D005260:Female; D019398:Genes, BRCA1; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C494112:ELK1 protein, human; D006131:Growth Inhibitors; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D050807:ets-Domain Protein Elk-1