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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
Irminger, Irmgard
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
Full text
Article (Published version) (1 MB) - document accessible for UNIGE members only Limited access to UNIGE
Structures
Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique
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

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Deposited on : 2012-05-25

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