Abstract
Estrogen is involved in breast cancer risk, which is increased for BRCA1 mutation carriers, suggesting a role for BRCA1 in estrogen signaling. BRCA1 exerts its function through forming an E3 ubiquitin ligase with BARD1. We report that the estrogen receptor alpha is a target of the BRCA1-BARD1 ubiquitin ligase in vivo. BRCA1 and BARD1 are required for estrogen receptor alpha ubiquitination and degradation, and repression of either one leads to ERalpha accumulation, suggesting a feedback loop between BRCA1-BARD1 and estrogen receptor alpha, since BRCA1 and BARD1 are induced by estrogen receptor alpha. While the ubiquitin ligase activity maps to the N-terminal RING finger domains of BRCA1 and BARD1, we demonstrate that the BARD1 C-terminus is important for target recognition. Furthermore, a BARD1 isoform lacking the RING domain binds and stabilizes estrogen receptor alpha. Thus deficiencies of BRCA1 or BARD1 and/or upregulation of BARD1 isoforms lead to estrogen receptor alpha upregulation, providing a functional link between BRCA1 deficiency, estrogen signaling, and tumorigenesis.
2010 Elsevier Ltd. All rights reserved.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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BRCA1 Protein / chemistry
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BRCA1 Protein / metabolism*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Estrogen Receptor alpha / chemistry*
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Estrogen Receptor alpha / physiology*
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Estrogen Receptor beta / metabolism
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Feedback, Physiological*
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Female
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Humans
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Mutant Proteins / chemistry
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Mutant Proteins / metabolism
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Protein Interaction Domains and Motifs
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Multimerization
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Protein Stability
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Protein Transport
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RING Finger Domains
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Tumor Suppressor Proteins / chemistry
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin / genetics
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligase Complexes / metabolism*
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Ubiquitin-Protein Ligases / chemistry
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Ubiquitin-Protein Ligases / genetics*
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination
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Up-Regulation
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Uterine Cervical Neoplasms / genetics
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Uterine Cervical Neoplasms / metabolism
Substances
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BRCA1 Protein
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Estrogen Receptor alpha
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Estrogen Receptor beta
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Mutant Proteins
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Protein Isoforms
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Tumor Suppressor Proteins
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Ubiquitin
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Ubiquitin-Protein Ligase Complexes
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BARD1 protein, human
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Ubiquitin-Protein Ligases