en
Scientific article
Review
English

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

Published inInternational journal of biochemistry & cell biology, vol. 42, no. 5, p. 693-700
Publication date2010
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
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
Main files (1)
Article (Published version)
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Identifiers
ISSN of the journal1357-2725
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