Estrogen receptor (ER)β isoforms rather than ERα regulate corticotropin-releasing hormone promoter activity through an alternate pathway

William J Schouler Miller, Shotaro Suzuki, Lydia K. Miller, Robert J Handa, Rosalie M. Uht

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10628-10635
Number of pages8
JournalJournal of Neuroscience
Volume24
Issue number47
DOIs
StatePublished - Nov 24 2004
Externally publishedYes

Fingerprint

Corticotropin-Releasing Hormone
Estrogen Receptors
Protein Isoforms
Ligands
Glucocorticoids
Transcription Factor AP-1
Hypothalamus
Estrogens
Proteins
Transcription Factors
Immunohistochemistry
Neurons
Amino Acids

Keywords

  • Corticotropin-releasing hormone
  • Estradiol
  • Estrogen receptor α
  • Estrogen receptor β
  • Stress
  • Tamoxifen

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Estrogen receptor (ER)β isoforms rather than ERα regulate corticotropin-releasing hormone promoter activity through an alternate pathway. / Miller, William J Schouler; Suzuki, Shotaro; Miller, Lydia K.; Handa, Robert J; Uht, Rosalie M.

In: Journal of Neuroscience, Vol. 24, No. 47, 24.11.2004, p. 10628-10635.

Research output: Contribution to journalArticle

Miller, William J Schouler ; Suzuki, Shotaro ; Miller, Lydia K. ; Handa, Robert J ; Uht, Rosalie M. / Estrogen receptor (ER)β isoforms rather than ERα regulate corticotropin-releasing hormone promoter activity through an alternate pathway. In: Journal of Neuroscience. 2004 ; Vol. 24, No. 47. pp. 10628-10635.
@article{bda7e9b7a564433b973c44605bb584f7,
title = "Estrogen receptor (ER)β isoforms rather than ERα regulate corticotropin-releasing hormone promoter activity through an alternate pathway",
abstract = "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.",
keywords = "Corticotropin-releasing hormone, Estradiol, Estrogen receptor α, Estrogen receptor β, Stress, Tamoxifen",
author = "Miller, {William J Schouler} and Shotaro Suzuki and Miller, {Lydia K.} and Handa, {Robert J} and Uht, {Rosalie M.}",
year = "2004",
month = "11",
day = "24",
doi = "10.1523/JNEUROSCI.5540-03.2004",
language = "English (US)",
volume = "24",
pages = "10628--10635",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "47",

}

TY - JOUR

T1 - Estrogen receptor (ER)β isoforms rather than ERα regulate corticotropin-releasing hormone promoter activity through an alternate pathway

AU - Miller, William J Schouler

AU - Suzuki, Shotaro

AU - Miller, Lydia K.

AU - Handa, Robert J

AU - Uht, Rosalie M.

PY - 2004/11/24

Y1 - 2004/11/24

N2 - 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.

AB - 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.

KW - Corticotropin-releasing hormone

KW - Estradiol

KW - Estrogen receptor α

KW - Estrogen receptor β

KW - Stress

KW - Tamoxifen

UR - http://www.scopus.com/inward/record.url?scp=9344221088&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=9344221088&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.5540-03.2004

DO - 10.1523/JNEUROSCI.5540-03.2004

M3 - Article

VL - 24

SP - 10628

EP - 10635

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 47

ER -