Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 104 (14): 5794-5799

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

Estrogen receptor {alpha} is a putative substrate for the BRCA1 ubiquitin ligase

Catherine M. Eakin{dagger}, Michael J. MacCoss{ddagger}, Gregory L. Finney{ddagger}, and Rachel E. Klevit{dagger},§

Departments of {dagger}Biochemistry and {ddagger}Genome Sciences, University of Washington, Seattle, WA 98195

Edited by Mary-Claire King, University of Washington, Seattle, WA, and approved February 9, 2007

Received for publication December 7, 2006.

Abstract: 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 ER{alpha} 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.

Key Words: breast cancer • ubiquitylation • ubiquitination • steroid hormone receptor

Author contributions: C.M.E. and R.E.K. designed research; C.M.E. performed research; C.M.E., M.J.M., and G.L.F. contributed new reagents/analytic tools; C.M.E. and M.J.M. analyzed data; and C.M.E. and R.E.K. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0610887104/DC1.

§To whom correspondence should be addressed. E-mail: klevit{at}u.washington.edu

© 2007 by The National Academy of Sciences of the USA

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Derailed Estrogen Signaling and Breast Cancer: An Authentic Couple.
B. Manavathi, O. Dey, V. N. R. Gajulapalli, R. S. Bhatia, S. Bugide, and R. Kumar (2013)
Endocr. Rev. 34, 1-32
   Abstract »    Full Text »    PDF »
ER{alpha} Phosphorylation at Y537 by Src Triggers E6-AP-ER{alpha} Binding, ER{alpha} Ubiquitylation, Promoter Occupancy, and Target Gene Expression.
J. Sun, W. Zhou, K. Kaliappan, Z. Nawaz, and J. M. Slingerland (2012)
Mol. Endocrinol. 26, 1567-1577
   Abstract »    Full Text »    PDF »
Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen Receptor {alpha} Turnover and Functional Activity via the SCFSkp2 Proteasomal Complex.
S. Bhatt, Z. Xiao, Z. Meng, and B. S. Katzenellenbogen (2012)
Mol. Cell. Biol. 32, 1928-1943
   Abstract »    Full Text »    PDF »
Cracking the Estrogen Receptor's Posttranslational Code in Breast Tumors.
M. Le Romancer, C. Poulard, P. Cohen, S. Sentis, J.-M. Renoir, and L. Corbo (2011)
Endocr. Rev. 32, 597-622
   Abstract »    Full Text »    PDF »
The UBXN1 Protein Associates with Autoubiquitinated Forms of the BRCA1 Tumor Suppressor and Inhibits Its Enzymatic Function.
F. Wu-Baer, T. Ludwig, and R. Baer (2010)
Mol. Cell. Biol. 30, 2787-2798
   Abstract »    Full Text »    PDF »
The hinge region of the human estrogen receptor determines functional synergy between AF-1 and AF-2 in the quantitative response to estradiol and tamoxifen.
W. Zwart, R. de Leeuw, M. Rondaij, J. Neefjes, M. A. Mancini, and R. Michalides (2010)
J. Cell Sci. 123, 1253-1261
   Abstract »    Full Text »    PDF »
Indole-3-Carbinol Triggers Aryl Hydrocarbon Receptor-dependent Estrogen Receptor (ER){alpha} Protein Degradation in Breast Cancer Cells Disrupting an ER{alpha}-GATA3 Transcriptional Cross-Regulatory Loop.
C. N. Marconett, S. N. Sundar, K. M. Poindexter, T. R. Stueve, L. F. Bjeldanes, and G. L. Firestone (2010)
Mol. Biol. Cell 21, 1166-1177
   Abstract »    Full Text »    PDF »
BRCA1 Regulates Acetylation and Ubiquitination of Estrogen Receptor-{alpha}.
Y. Ma, S. Fan, C. Hu, Q. Meng, S. A. Fuqua, R. G. Pestell, Y. A. Tomita, and E. M. Rosen (2010)
Mol. Endocrinol. 24, 76-90
   Abstract »    Full Text »    PDF »
Ubiquitination and Downregulation of BRCA1 by Ubiquitin-Conjugating Enzyme E2T Overexpression in Human Breast Cancer Cells.
T. Ueki, J.-H. Park, T. Nishidate, K. Kijima, K. Hirata, Y. Nakamura, and T. Katagiri (2009)
Cancer Res. 69, 8752-8760
   Abstract »    Full Text »    PDF »
Mechanism of BRCA1-Mediated Inhibition of Progesterone Receptor Transcriptional Activity.
P. Katiyar, Y. Ma, A. Riegel, S. Fan, and E. M. Rosen (2009)
Mol. Endocrinol. 23, 1135-1146
   Abstract »    Full Text »    PDF »
OTU Domain-containing Ubiquitin Aldehyde-binding Protein 1 (OTUB1) Deubiquitinates Estrogen Receptor (ER) {alpha} and Affects ER{alpha} Transcriptional Activity.
V. Stanisic, A. Malovannaya, J. Qin, D. M. Lonard, and B. W. O'Malley (2009)
J. Biol. Chem. 284, 16135-16145
   Abstract »    Full Text »    PDF »
Liver X Receptor Ligands Suppress Ubiquitination and Degradation of LXR{alpha} by Displacing BARD1/BRCA1.
K. H. Kim, J. M. Yoon, A H. Choi, W. S. Kim, G. Y. Lee, and J. B. Kim (2009)
Mol. Endocrinol. 23, 466-474
   Abstract »    Full Text »    PDF »
Estrogen Receptor-{alpha} Hinge-Region Lysines 302 and 303 Regulate Receptor Degradation by the Proteasome.
N. B. Berry, M. Fan, and K. P. Nephew (2008)
Mol. Endocrinol. 22, 1535-1551
   Abstract »    Full Text »    PDF »
Phosphorylation of Activation Function-1 Regulates Proteasome-Dependent Nuclear Mobility and E6-Associated Protein Ubiquitin Ligase Recruitment to the Estrogen Receptor {beta}.
N. Picard, C. Charbonneau, M. Sanchez, A. Licznar, M. Busson, G. Lazennec, and A. Tremblay (2008)
Mol. Endocrinol. 22, 317-330
   Abstract »    Full Text »    PDF »
Oncogenic BARD1 Isoforms Expressed in Gynecological Cancers.
L. Li, S. Ryser, E. Dizin, D. Pils, M. Krainer, C. E. Jefford, F. Bertoni, R. Zeillinger, and I. Irminger-Finger (2007)
Cancer Res. 67, 11876-11885
   Abstract »    Full Text »    PDF »
BRCA1 Control of Steroid Receptor Ubiquitination.
G. F. Heine and J. D. Parvin (2007)
Sci. STKE 2007, pe34
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882