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Title

Negative feedback loop of BRCA1-BARD1 ubiquitin ligase on estrogen receptor alpha stability and activity antagonized by cancer-associated isoform of BARD1

Authors
Dizin, Eva
Published in International Journal of Biochemistry & Cell Biology. 2010, vol. 42, no. 5, p. 693-700
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.
Keywords BRCA1 Protein/chemistry/metabolismBreast Neoplasms/genetics/metabolismCell Line, TumorEstrogen Receptor alpha/chemistry/physiologyEstrogen Receptor beta/metabolismFeedback, PhysiologicalFemaleHumansMutant Proteins/chemistry/metabolismProtein Interaction Domains and MotifsProtein Isoforms/chemistry/genetics/metabolismProtein MultimerizationProtein StabilityProtein TransportRING Finger DomainsTumor Suppressor Proteins/chemistry/genetics/metabolismUbiquitin/genetics/metabolismUbiquitin-Protein Ligase Complexes/metabolismUbiquitin-Protein Ligases/chemistry/genetics/metabolismUbiquitinationUp-RegulationUterine Cervical Neoplasms/genetics/metabolism
Identifiers
PMID: 20060929
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DIZIN, Eva, IRMINGER, Irmgard. Negative feedback loop of BRCA1-BARD1 ubiquitin ligase on estrogen receptor alpha stability and activity antagonized by cancer-associated isoform of BARD1. In: International Journal of Biochemistry & Cell Biology, 2010, vol. 42, n° 5, p. 693-700. https://archive-ouverte.unige.ch/unige:21433

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Deposited on : 2012-05-25

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