Long-Range Activation of GREB1 by Estrogen Receptor via Three Distal Consensus Estrogen-Responsive Elements in Breast Cancer Cells
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The estrogen receptor (ER) binds to estrogen-responsive elements (EREs) to activate gene transcription. The best characterized EREs are located in proximal gene promoters, but recent data indicate that only a minority of ER binding sites lie within proximal promoter regions. GREB1 (gene regulated by estrogen in breast cancer 1) is an ER target gene that regulates estrogen-induced proliferation in breast cancer cells. We identified three consensus EREs, located at −21.2, −9.5, and −1.6 kb upstream of the closest GREB1a transcription start site that appear to mediate long-range GREB1 gene activation by ER. All three ERE sites nucleate ER, steroid receptor coactivator-3 (SRC-3), and RNA polymerase II (Pol II) and undergo histone acetylation in response to estradiol. Estrogen-stimulated ER binding at all three EREs was cyclic and synchronous. SRC-3 and Pol II recruitment to all three EREs was activated by estrogen but not tamoxifen. In contrast, estrogen stimulated only Pol II and not ER or SRC-3 recruitment to the GREB1 core promoter regions. Long-range histone acetylation, centered on the three ERE motifs and the GREB1 core promoters, was observed in response to estrogen but not to tamoxifen. These data suggest that estrogen-stimulated GREB1 transcription may involve coordinated ER binding to all three distal consensus ERE motifs. Long-range activation by ER acting at multiple EREs may be more common than previously appreciated.
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Regulation of GREB1 transcription by oestrogen receptor α (ERα) is mediated through three oestrogen response elements (EREs) located 20 kb upstream of the gene.
“Regulation of GREB1 transcription by oestrogen receptor α (ERα) is mediated through three oestrogen response elements (EREs) located 20 kb upstream of the gene5051.”
From Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism (2017) · cites this paper as [51]
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- Authors
- Sun, J., Nawaz, Z., & Slingerland, J. M.
- Affiliations
- Braman Family Breast Cancer Institute (J.S., Z.N., J.M.S.),Miami, Florida 33136
- University of Miami (US)
- Corresponding author
- Sun, Jun
- Slingerland, Joyce M.
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2007-11-01
- Volume
- 21
- Issue
- 11
- Pages
- 2651-2662
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2153843576
- Cited by
- 83
- References
- 40
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 4 · 2021: 5 · 2020: 9 · 2019: 6 · 2018: 5 · 2017: 4 · 2016: 2 · 2015: 5 · 2014: 8 · 2013: 2 · 2012: 8
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Miami
- Sylvester Comprehensive Cancer Center, University of Miami Health Systems
- Leonard M. Miller School of Medicine
- 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
- GREB1, estrogen receptor, estrogen response element, breast cancer cells, SRC-3, RNA polymerase II recruitment, histone acetylation, estradiol, tamoxifen, transcriptional regulation, core promoter
- MeSH terms
- Base Sequence, Breast Neoplasms, Enzyme Activation, Estradiol, Estrogens, Humans, Molecular Sequence Data, Neoplasm Proteins, Promoter Regions, Genetic, Receptors, Estrogen, Tamoxifen, Transcription, Genetic, Trans-Activators, Amino Acid Motifs, Cell Line, Tumor, Histone Acetyltransferases, Nuclear Receptor Coactivator 3
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