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.
Dizin
Eva
E
Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland.
Irminger-Finger
Irmgard
I
D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D006801:Humans; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D055550:Protein Stability; D021381:Protein Transport; D054829:RING Finger Domains; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism
D019313:BRCA1 Protein; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D050505:Mutant Proteins; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D043743:Ubiquitin-Protein Ligase Complexes; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases