期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 14, 页码 5794-5799出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0610887104
关键词
breast cancer; ubiquitylation; ubiquitination; steroid hormone receptor
资金
- NCI NIH HHS [1R01CA79953, R01 CA079953] Funding Source: Medline
- NCRR NIH HHS [P41RR011823, P41 RR011823] Funding Source: Medline
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 (ER alpha) transcriptional activation by BRCA1. Here, we show that ERa is a putative substrate for the BRCA1/BARD1 ubiquitin ligase, suggesting a possible mechanism for regulation of ER alpha activity by BRCA1. Our results show ER alpha is predominantly monoubiquitinated in a reaction that involves interactions with both BRCA1 and BARD1. The regions of BRCA1/BARD1 necessary for ER alpha 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 ER alpha ubiquitination. The identification of ER alpha as a putative BRCA1/BARD1 ubiquitination substrate reveals a potential link between the loss of BRCA1/BARD1 ligase activity and tissue-specific carcinoma.
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