Sci. STKE, 10 April 2007
Ubiquitin Ubiquitination of Estrogen Receptor by BRCA1
John F. Foley
Sciences STKE, AAAS, Washington, DC 20005, USA
The breast cancer suppressor protein BRCA1 is associated with all forms of breast cancer. BRCA1 is an E3 ubiquitin ligase, but none of its known targets explains the association of BRCA1 with breast tumors. BRCA1 must form a heterodimer with BARD1 to have ligase activity. Estrogen receptor (ER) is a transcription factor, which, after binding to its ligand, estrogen, forms functional dimers that bind to the promoter regions of target genes to promote transcriptional activation. ER shares an expression profile with BRCA1-associated tumors, and BRCA1 regulates the transcriptional activation of ER, so Eakin et al. investigated the relationship between BRCA1 and ER. They used in vitro ubiquitination assays with purified recombinant proteins, followed by Western blotting, to show that the ligand-binding domain (LBD) of ER was ubiquitinated by BRCA1/BARD1. The authors went on to determine the regions of both BRCA1 and BARD1 that were necessary for this activity. BRCA1/BARD1 was shown to ubiquitinate ER whether it was bound to an agonist, estrogen, or to an antagonist, tamoxifen. ER-LBD was not ubiquitinated by BRCA1/BARD complexes containing mutant BRCA1 proteins that had the same mutations as are observed in patients with breast cancer, which suggests that the association of these BRCA1 mutations with breast cancer may be due to disruption in the ubiquitination of ER. BRCA1/BARD1 activity resulted in monoubiquitination of ER, a modification associated with regulating activity rather than promoting degradation. This study provides a mechanism whereby BRCA1 mutations may be linked to breast cancer development.
C. M. Eakin, M. J. MacCoss, G. L. Finney, R. E. Klevit, Estrogen receptor is a putative substrate for the BRCA1 ubiquitin ligase. Proc. Natl. Acad. Sci. U.S.A. 104, 5794-5799 (2007). [Abstract] [Full Text]
Citation: J. F. Foley, Ubiquitination of Estrogen Receptor by BRCA1. Sci. STKE 2007, tw125 (2007).
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