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PMID: 15342491 Published · ppublish English Comparative Study Journal Article Research Support, U.S. Gov't, P.H.S.

Attenuation of estrogen receptor alpha-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor.

Genes & development ·Vol. 18 ·No. 17 ·2004-09-01 ·Pages 2134-46

Aiyar SE, Sun JL, Blair AL, Moskaluk CA, Lu YZ, Ye QN, Yamaguchi Y, Mukherjee A, Ren DM, Handa H, Li R

Abstract

Estrogen receptor alpha (ERalpha) signaling is paramount for normal mammary gland development and function and the repression of breast cancer. ERalpha function in gene regulation is mediated by a number of coactivators and corepressors, most of which are known to modify chromatin structure and/or influence the assembly of the regulatory complexes at the level of transcription initiation. Here we describe a novel mechanism of attenuating the ERalpha activity. We show that cofactor of BRCA1 (COBRA1), an integral subunit of the human negative elongation factor (NELF), directly binds to ERalpha and represses ERalpha-mediated transcription. Reduction of the endogenous NELF proteins in breast cancer cells using small interfering RNA results in elevated ERalpha-mediated transcription and enhanced cell proliferation. Chromatin immunoprecipitation reveals that recruitment of COBRA1 and the other NELF subunits to endogenous ERalpha-responsive promoters is greatly stimulated upon estrogen treatment. Interestingly, COBRA1 does not affect the estrogen-dependent assembly of transcription regulatory complexes at the ERalpha-regulated promoters. Rather, it causes RNA polymerase II (RNAPII) to pause at the promoter-proximal region, which is consistent with its in vitro biochemical activity. Therefore, our in vivo work defines the first corepressor of nuclear receptors that modulates ERalpha-dependent gene expression by stalling RNAPII. We suggest that this new level of regulation may be important to control the duration and magnitude of a rapid and reversible hormonal response.

MeSH Terms
Blotting, Northern Cells, Cultured Chromatin/metabolism Estrogen Receptor alpha Gene Expression Regulation/physiology Humans Immunohistochemistry Luciferases Nuclear Proteins/metabolism Plasmids/genetics Precipitin Tests Promoter Regions, Genetic/genetics RNA Polymerase II/metabolism RNA, Small Interfering/genetics,metabolism Receptors, Estrogen/genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Transcription Factors/metabolism Transfection
Chemicals
Chromatin Estrogen Receptor alpha Nuclear Proteins RNA, Small Interfering Receptors, Estrogen Transcription Factors negative elongation factor Luciferases RNA Polymerase II
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Aiyar Sarah E
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, Virginia 22908-0733, USA.
Sun Jian-long
Blair Ashley L
Moskaluk Christopher A
Lu Yun-zhe
Ye Qi-Nong
Yamaguchi Yuki
Mukherjee Amitava
Ren Da-ming
Handa Hiroshi
Li Rong
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1214104
Published
2004-09-01
Pages
2134-46
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC515291
Subset
IM
Grants
NCI NIH HHS · F32 CA099359 · United States
NIDDK NIH HHS · R01 DK064604 · United States
NCI NIH HHS · 1F32CA99359-01 · United States
External Links
PubMed source DOI: 10.1101/gad.1214104 PMC Full Text View journal details
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