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PNAS 102 (37): 13153-13157

Copyright © 2005 by the National Academy of Sciences.

CELL BIOLOGY

Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes

Jonna Frasor *, Jeanne M. Danes *, Cory C. Funk {dagger}, and Benita S. Katzenellenbogen *, {dagger}, {ddagger}

Departments of *Molecular and Integrative Physiology and {dagger}Cell and Structural Biology, University of Illinois at Urbana–Champaign, Urbana, IL 61801

Edited by Pierre Chambon, Institute of Genetics and Molecular and Cellular Biology, Strasbourg, France, and approved August 2, 2005

Received for publication April 4, 2005.

Abstract: The nuclear receptor corepressor N-CoR plays a crucial role in the repressive activity of diverse transcription factors, yet little is known about what regulates its cellular level. We have found that estrogen markedly down-regulates N-CoR protein levels in estrogen receptor (ER)-positive breast cancer cells without affecting N-CoR mRNA levels, whereas levels of the related corepressor SMRT are unaffected. This effect is attributable to estrogen up-regulation of the ubiquitin ligase Siah2, which is a rapid and primary transcriptional response mediated by the ER, and precedes the loss of N-CoR. Treatment with proteasomal inhibitor or with small interfering RNA against Siah2 prevented the down-regulation of N-CoR by estrogen. Furthermore, the expression of 24-hydroxylase, a gene repressed by unliganded vitamin D receptor through its interaction with N-CoR, was up-regulated by estrogen and required Siah2. Our results illustrate a mechanism by which the estrogen–ER complex markedly reduces the level of N-CoR through a process involving the up-regulation of Siah2 and the subsequent targeting of N-CoR for proteasomal degradation. These findings reveal that, although estrogen directly regulates the transcription of many genes, by regulating a gene such as Siah2 it can exert profound "secondary" effects on cellular activity through mechanisms such as targeting regulatory proteins for degradation. This estrogen-evoked down-regulation of N-CoR could have a global derepressive effect on genes whose repression depends on N-CoR and thereby have broad impact on the activity of transcription factors and nuclear receptors whose actions involve N-CoR.

Key Words: breast cancer • estrogen receptor • proteasome • Siah2

Author contributions: J.F. and B.S.K. designed research; J.F., J.M.D., and C.C.F. performed research; J.F., J.M.D., C.C.F., and B.S.K. analyzed data; and J.F. and B.S.K. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: E2, 17{beta}-estradiol; ER, estrogen receptor; VDR, vitamin D receptor; Vit D3, 1,25-dihydroxyvitamin D3; siRNA, small interfering RNA.

{ddagger} To whom correspondence should be addressed at: Department of Molecular and Integrative Physiology, University of Illinois, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, IL 61801-3704. E-mail: katzenel{at}uiuc.edu.

© 2005 by The National Academy of Sciences of the USA

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