Estrogen receptor alpha is a putative substrate for the BRCA1 ubiquitin ligase.
The breast cancer suppressor protein, BRCA1, is a ubiquitin ligase expressed in a wide range of tissues. However, inheritance of a single BRCA1 mutation significantly increases a woman's lifetime chance of developing tissue-specific cancers in the breast and ovaries. Recently, studies have suggested this tissue specificity may be linked to inhibition of estrogen receptor alpha (ERalpha) transcriptional activation by BRCA1. Here, we show that ERalpha is a putative substrate for the BRCA1/BARD1 ubiquitin ligase, suggesting a possible mechanism for regulation of ERalpha activity by BRCA1. Our results show ERalpha is predominantly monoubiquitinated in a reaction that involves interactions with both BRCA1 and BARD1. The regions of BRCA1/BARD1 necessary for ERalpha ubiquitination include the RING domains and at least 241 and 170 residues of BRCA1 and BARD1, respectively. Cancer-predisposing mutations in BRCA1 are observed to abrogate ERalpha ubiquitination. The identification of ERalpha as a putative BRCA1/BARD1 ubiquitination substrate reveals a potential link between the loss of BRCA1/BARD1 ligase activity and tissue-specific carcinoma.
Eakin
Catherine M
CM
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Maccoss
Michael J
MJ
Finney
Gregory L
GL
Klevit
Rachel E
RE
D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D001665:Binding Sites; D004926:Escherichia coli / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*
D019313:BRCA1 Protein; D047628:Estrogen Receptor alpha; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases