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Estrogen Receptor (ER)β Isoforms Rather Than ERα Regulate Corticotropin-Releasing Hormone Promoter Activity through an Alternate Pathway
Open accessAbstract
The hypothalamic-pituitary-adrenal axis regulates mammalian stress responses by secreting glucocorticoids. The magnitude of the response is in part determined by gender, for in response to a given stressor, circulating glucocorticoids reach higher levels in female rats than in males. This gender difference could result from estrogen regulation of the corticotropin-releasing hormone (CRH) promoter via either of its receptors: estrogen receptor (ER)α or ERβ. Immunocytochemistry revealed that a subset (12%) of medial parvocellular CRH neurons in the rat hypothalamus contain ERβ but not ERα. To determine whether ERs could regulate CRH promoter activity, we cotransfected cells with a CRH promoter construct and either ERα or individual ERβ isoforms. ERα weakly stimulated CRH promoter transcriptional activity in a ligand-independent manner. Conversely, all ERβ isoforms tested stimulated CRH promoter activity with different ligand profiles. ERβ1 and ERβ2δ3 displayed constitutive activity (ERβ1 more than ERβ2δ3). Ligand-dependent activity of β isoforms 1 and 2 was altered by an Exon3 splice variant (δ3) or by the additional 18 amino acids in the ligand-binding domain of ERβ2 isoforms. Lastly, we suggest that ER regulation of CRH takes place through an alternate pathway, one that requires protein-protein interactions with other transcription factors or their associated complexes. However, a pure ER-activator protein-1 alternate pathway does not appear to be involved.
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ERβ can bind the Crh promoter to regulate transcription.
“Later in vitro studies by Miller et al. (2004) used the Crh proximal promoter in transformed rat hypothalamic neurons to show that ERβ can bind the Crh promoter to regulate transcription (Miller, Suzuki, Miller, Handa, & Uht, 2004).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Miller, Suzuki, Miller, Handa, & Uht, 2004
The Results section (‘ERβ isoforms elicit different patterns of CRH promoter regulation’; page not provided) reports that ERβ1 activated a CRH promoter reporter, supporting transcriptional regulation. It does not establish that ERβ binds the promoter. The Transcription experiments section (page not provided) describes transfected HeLa cells, not transformed rat hypothalamic neurons. (LLM, conf=0.90)
Experimental — accuracy not yet measuredEstrogens regulate Crh gene and promoter activity.
“The Crh gene and promoter activity have been shown to be regulated by estrogens”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Miller, Suzuki, Miller, Handa, & Uht, 2004
In vitro, estrogen receptor β but not α strongly stimulates the Crh promoter.
“In vitro studies have shown that the estrogen receptor β, but not α, has a strong stimulatory action on the Crh promoter”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Miller, Suzuki, Miller, Handa, & Uht, 2004
Regulation of the Crh promoter by ERα is weak.
“Of importance, regulation by ERα was weak (Miller, Suzuki, Miller, Handa, & Uht, 2004).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Miller, Suzuki, Miller, Handa, & Uht, 2004
The Crh promoter is differentially regulated by splice variants of ERβ.
“In addition, the Crh promoter was differentially regulated by splice variants of ERβ, consistent with the demonstration that a variant that lacks the full DNA binding domain (ERβ1 delta3) could signal through non-classical mechanisms by protein: protein interactions involving an SP1 element rather than an ERE (Price et al., 2001).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Miller, Suzuki, Miller, Handa, & Uht, 2004
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Metadata
- Authors
- Miller, W. J. S., Suzuki, S., Miller, L. K., Handa, R., & Uht, R. M.
- Affiliations
- University of Virginia (US)
- Colorado State University (US)
- Corresponding author
- Uht, Rosalie M.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-11-24
- Volume
- 24
- Issue
- 47
- Pages
- 10628-10635
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6730133
- OpenAlex
- W2149088240
- Cited by
- 97
- References
- 4
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 5 · 2019: 2 · 2018: 4 · 2017: 6 · 2016: 6 · 2015: 7 · 2014: 2 · 2013: 4 · 2012: 4
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- National Cancer Institute (P01CA095616)
- National Institute of Neurological Disorders and Stroke (R01NS039951)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- estrogen receptor beta, estrogen receptor alpha, corticotropin-releasing factor, hypothalamic-pituitary-adrenal axis, stress response, ERβ isoforms, ligand-binding domain, transcriptional regulation, AP-1 pathway
- MeSH terms
- Animals, Corticotropin-Releasing Hormone, Female, Gene Expression Regulation, HeLa Cells, Humans, Immunohistochemistry, Paraventricular Hypothalamic Nucleus, Promoter Regions, Genetic, Transcription, Genetic, Rats, Sprague-Dawley, Transcription Factor AP-1, Protein Isoforms, Estrogen Receptor alpha, Estrogen Receptor beta, Rats
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