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

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.
Mesh Terms:
BRCA1 Protein, Breast Neoplasms, Cell Line, Tumor, Estrogen Receptor alpha, Estrogen Receptor beta, Feedback, Physiological, Female, Humans, Mutant Proteins, Protein Interaction Domains and Motifs, Protein Isoforms, Protein Multimerization, Protein Stability, Protein Transport, RING Finger Domains, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Ubiquitination, Up-Regulation, Uterine Cervical Neoplasms
Int. J. Biochem. Cell Biol.
Date: May. 01, 2010
Download Curated Data For This Publication
125557
Switch View:
  • Interactions 6
  • PTM Genes 1