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BRCA1 splice variants exhibit overlapping and distinct transcriptional transactivation activities
Author(s) -
McEachern Kristen A.,
Archey William B.,
Douville Karen,
Arrick Bradley A.
Publication year - 2003
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.10487
Subject(s) - transactivation , promoter , biology , microbiology and biotechnology , transfection , exon , alternative splicing , mutant , gene isoform , transcriptional regulation , gene expression , gene , genetics
Abstract The global changes in gene expression induced by transient increased expression of full length BRCA1 as well as the spliced variant BRCA1 S were evaluated by cDNA expression array in a human non‐tumorigenic mammary epithelial cell line, MCF10A. Over 30 genes were identified that displayed an altered expression pattern in response to the expression of BRCA1 splice variants. The expression of NFκB inducing kinase was markedly down‐regulated in BRCA1 L transfected cells. However, a NFκB‐responsive promoter construct yielded increased basal activity in BRCA1 L transfected cells, as well as following treatment with tumor necrosis factor‐α or lymphotoxin. In addition, nuclear extracts from BRCA1 L transfected cells displayed increased DNA binding to the κB consensus site. The transcriptional activity of a panel of promoter constructs was evaluated following expression of wild type or mutant BRCA1. Full length BRCA1 transactivated the estrogen receptor‐α (ERα) and BCL2 promoters as well as AP‐1, SRE, and CRE containing promoters. Transactivation activity of the exon 11‐deleted BRCA1 S was more limited and usually of lower magnitude. The ability of a pathogenic mutation, 5382insC, to abrogate the transcriptional transactivation by BRCA1 L and BRCA1 S was also investigated. Mutant BRCA1 retained wild type levels of transcriptional activity for the ERα promoter as well as for the NFκB, AP‐1, and CRE‐responsive promoters but had reduced or no activity with the BCL2 and SRE promoters. These results show that BRCA1 isoforms have both overlapping and distinct transcriptional transactivation activity, and that a mutant form of BRCA1 implicated in carcinogenesis is not devoid of all activity. J. Cell. Biochem. 89: 120–132, 2003. © 2003 Wiley‐Liss, Inc.