title: BRCA1/BARD1 complex interacts with steroidogenic factor 1--A potential mechanism for regulation of aromatase expression by BRCA1.
abstract: Germline mutations in BRCA1 predispose women to early onset of breast and ovarian cancers. Findings from previous studies support the notion that the tissue- and gender-specific tumor suppression function of BRCA1 is associated with its role in negative regulation of aromatase expression, the rate-limiting step in estrogen biosynthesis. The molecular mechanism of BRCA1 in regulating aromatase promoter activity remains to be elucidated. In this study, we demonstrate that, in an ovarian granulosa cell line KGN, steroidogenic factor 1 (SF-1) is required for aromatase PII promoter basal activity as well as the elevated aromatase expression mediated by BRCA1 knockdown. Furthermore, BRCA1 in KGN cells exists mainly as a heterodimer with BARD1. We provide evidence that the BRCA1/BARD1 complex interacts with SF-1 both in vivo and in vitro. However, the intrinsic ubiquitin E3 ligase activity of BRCA1/BARD1 does not appear to contribute to ubiquitynation of SF-1. We propose that the interaction between SF-1 and BRCA1/BARD1 may recruit BRCA1/BARD1 complex to the aromatase PII promoter for BRCA1/BARD1-mediate transcriptional repression.
authors.affiliation: Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245, USA.
authors.forename: Yunzhe
authors.initials: Y
authors.lastname: Lu
authors.forename: Tao
authors.initials: T
authors.lastname: Kang
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Hu
mesh_terms: D001141:Aromatase / Q000235:genetics*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; D054339:Steroidogenic Factor 1; D025521:Tumor Suppressor Proteins; D001141:Aromatase; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases