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Cited by 84Estrogen and related hormone effectsGenomics and Chromatin DynamicsEpigenetics and DNA Methylation

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

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Frasor, Jonna, Danes, Jeanne M., Funk, Cory C., Katzenellenbogen, Benita S.·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0502782102PMC PMC1201577
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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.

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Authors
Frasor, J., Danes, J. M., Funk, C. C., & Katzenellenbogen, B. S.
Affiliations
University of Illinois Urbana-Champaign (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-09
Volume
102
Issue
37
Pages
13153-13157
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0502782102
PMC
PMC1201577
OpenAlex
W2035266044
Cited by
82
References
36
Citations by year
2024: 1 · 2023: 2 · 2021: 1 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 5 · 2016: 10 · 2015: 3 · 2014: 4 · 2013: 7 · 2012: 6
FWCI
3.07
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Breast Cancer Research Foundation
  • National Institutes of Health
  • National Cancer Institute (CA 18119, R01CA018119, R01CA130932)
  • National Institute of Environmental Health Sciences (T32-ES07326, T32ES007326)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
NCoR, SMRT, estrogen receptor, SIAH2, ubiquitin ligase, proteasomal degradation, protein stability, estrogen receptor-positive breast cancer, 24-hydroxylase, vitamin D receptor, transcriptional derepression, nuclear receptor corepressor
MeSH terms
Seven in Absentia Proteins, Cysteine Endopeptidases, Estrogens, Female, Humans, Nuclear Proteins, Receptors, Estrogen, Repressor Proteins, RNA, Messenger, Transcription Factors, Down-Regulation, Up-Regulation, Ubiquitin-Protein Ligases, Cell Line, Tumor, Nuclear Receptor Co-Repressor 1

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