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Negative feedback loop of BRCA1-BARD1 ubiquitin ligase on estrogen receptor alpha stability and activity antagonized by cancer-associated isoform of BARD1 |
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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/metabolism — Breast Neoplasms/genetics/metabolism — Cell Line, Tumor — Estrogen Receptor alpha/chemistry/physiology — Estrogen Receptor beta/metabolism — Feedback, Physiological — Female — Humans — Mutant Proteins/chemistry/metabolism — Protein Interaction Domains and Motifs — Protein Isoforms/chemistry/genetics/metabolism — Protein Multimerization — Protein Stability — Protein Transport — RING Finger Domains — Tumor Suppressor Proteins/chemistry/genetics/metabolism — Ubiquitin/genetics/metabolism — Ubiquitin-Protein Ligase Complexes/metabolism — Ubiquitin-Protein Ligases/chemistry/genetics/metabolism — Ubiquitination — Up-Regulation — Uterine Cervical Neoplasms/genetics/metabolism | |
Identifiers | PMID: 20060929 | |
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Citation (ISO format) | 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. doi: 10.1016/j.biocel.2009.12.025 https://archive-ouverte.unige.ch/unige:21433 |