Editors' ChoiceUbiquitin

Ubiquitination of Estrogen Receptor α by BRCA1

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Science's STKE  10 Apr 2007:
Vol. 2007, Issue 381, pp. tw125
DOI: 10.1126/stke.3812007tw125

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 α (ERα) 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. ERα shares an expression profile with BRCA1-associated tumors, and BRCA1 regulates the transcriptional activation of ERα, so Eakin et al. investigated the relationship between BRCA1 and ERα. They used in vitro ubiquitination assays with purified recombinant proteins, followed by Western blotting, to show that the ligand-binding domain (LBD) of ERα 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 ERα whether it was bound to an agonist, estrogen, or to an antagonist, tamoxifen. ERα-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 ERα. BRCA1/BARD1 activity resulted in monoubiquitination of ERα, 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 α is a putative substrate for the BRCA1 ubiquitin ligase. Proc. Natl. Acad. Sci. U.S.A. 104, 5794-5799 (2007). [Abstract] [Full Text]

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