Mitochondrial localization, ELK-1 transcriptional regulation and growth inhibitory functions of BRCA1, BRCA1a, and BRCA1b proteins.
Mitochondrial localization, ELK-1 transcriptional regulation and growth inhibitory functions of BRCA1, BRCA1a, and BRCA1b proteins.
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DOI：
10.1002/jcp.21708
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发表时间：
2009-06
影响因子：
5.6
通讯作者：
Rao, Veena N.
中科院分区：
文献类型：
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作者：
Maniccia, Anna W.;Lewis, Catherine;Begum, Nurjahan;Xu, Jingyao;Cui, Jianqi;Chipitsyna, Galina;Aysola, Kartik;Reddy, Vaishali;Bhat, Ganapathy;Fujimura, Yasuo;Henderson, Beric;Reddy, E. Shyam P.;Rao, Veena N.
BRCA1是一种肿瘤抑制基因，在乳腺癌和卵巢癌家族中发生突变。在不同的组织中发现了几种BRCA1剪接变体，但目前对它们的亚细胞定位和功能知之甚少。我们之前描述了BRCA1剪接变异体BRCA1a可以诱导细胞凋亡，并作为三重阴性乳腺癌、卵巢癌和前列腺癌的肿瘤抑制因子。在这项研究中，我们分析了BRCA1亚型(BRCA1a和BRCA1b)的功能，并将它们与野生型BRCA1蛋白进行了比较，包括通过核糖核酸酶保护实验研究BRCA1在正常细胞和肿瘤细胞中的表达，通过免疫荧光显微镜和蛋白质印迹分析进行亚细胞定位/分级，生物相关蛋白的转录调控和在乳腺癌细胞中的生长抑制。我们首次证明了异位表达的GFP标记的BRCA1、BRCA1a和BRCA1b蛋白定位于线粒体，抑制ELK-1的转录活性，并对乳腺癌细胞具有抗增殖活性。这些结果表明，含有P53、Rb、c-Myc、γ-微管蛋白、STAT、RAD51、RAD50结合域和血管生成素-1抑制域两种核定位信号的外显子9、10和11序列(AA263-1365)对于这些蛋白质的线粒体定位和生长抑制功能并不是绝对必需的。由于线粒体功能障碍是癌症的一个标志，我们可以推测，BRCA1蛋白的线粒体定位可能在调节线粒体DNA损伤和BRCA1蛋白的凋亡活性以及错误定位导致癌症方面具有重要的功能。
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, sub cellular 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, γ- tubulin, Stat, Rad 51, Rad 50 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.
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影响因子：
56.9
作者：
FUTREAL, PA;LIU, QY;WISEMAN, R
通讯作者：
WISEMAN, R
影响因子：
30.8
作者：
FRIEDMAN, LS;OSTERMEYER, EA;KING, MC
通讯作者：
KING, MC
影响因子：
8
作者：
Lu, ML;Arrick, BA
通讯作者：
Arrick, BA
影响因子：
64.8
作者：
HIPSKIND, RA;RAO, VN;NORDHEIM, A
通讯作者：
NORDHEIM, A
影响因子：
--
作者：
Chaise, F.
通讯作者：
Chaise, F.