Estrogen receptor β isoform-specific induction of transforming growth factor β-inducible early gene-1 in human osteoblast cells: An essential role for the activation function 1 domain

John R Hawse, Malayannan Subramaniam, David G Monroe, Amanda H. Hemmingsen, James N. Ingle, Sundeep Khosla, Merry Jo Oursler, Thomas C. Spelsberg

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The estrogen receptors (ER) α and β are important ligand-mediated transcription factors known to play significant biological roles in numerous tissues including bone. Despite the high homology shared by these receptors, recent studies have suggested that their function is largely unique. Although these receptors have been studied in detail for more than a decade, little data exist concerning the mechanisms by which these two proteins regulate distinct sets of genes. Using the TGFβ-inducible early gene-1 (TIEG) as a model, we demonstrate that TIEG is rapidly induced in response to estrogen in osteoblasts by ERβ, but not ERα. We have identified the regulatory elements utilized by ERβ and have demonstrated that ERβ recruits steroid receptor coactivator (SRC)1 and SRC2 to this regulatory region. Additionally, deletion of the ERβ-activation function 1 (AF1) domain drastically decreases the estrogen induction of TIEG. Through the use of chimeric receptors, we have demonstrated that the AF1 domain of ERβ is responsible for recruiting SRC1 and SRC2 and inducing the expression of TIEG in osteoblasts. Finally, SRC1, but not SRC2, is essential for TIEG induction by ERβ. Overall, these data demonstrate that the estrogen induction of TIEG is ERβ specific and that the AF1 domain of ERβ confers this specificity. Finally, a novel and important role for ERβ's AF1 is implicated in the recruitment of specific coactivators, suggesting that the AF1 may play a significant role in conferring the differences in regulation of gene expression by these two receptors.

Original languageEnglish (US)
Pages (from-to)1579-1595
Number of pages17
JournalMolecular Endocrinology
Volume22
Issue number7
DOIs
StatePublished - Jul 2008

Fingerprint

Transforming Growth Factors
Osteoblasts
Estrogen Receptors
Protein Isoforms
Genes
Estrogens
Nuclear Receptor Coactivator 2
Nuclear Receptor Coactivator 1
Nucleic Acid Regulatory Sequences
Gene Expression Regulation
Transcription Factors
Ligands
Bone and Bones

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Estrogen receptor β isoform-specific induction of transforming growth factor β-inducible early gene-1 in human osteoblast cells : An essential role for the activation function 1 domain. / Hawse, John R; Subramaniam, Malayannan; Monroe, David G; Hemmingsen, Amanda H.; Ingle, James N.; Khosla, Sundeep; Oursler, Merry Jo; Spelsberg, Thomas C.

In: Molecular Endocrinology, Vol. 22, No. 7, 07.2008, p. 1579-1595.

Research output: Contribution to journalArticle

@article{8683eabaf40f4a97ac857b8c6b87db1b,
title = "Estrogen receptor β isoform-specific induction of transforming growth factor β-inducible early gene-1 in human osteoblast cells: An essential role for the activation function 1 domain",
abstract = "The estrogen receptors (ER) α and β are important ligand-mediated transcription factors known to play significant biological roles in numerous tissues including bone. Despite the high homology shared by these receptors, recent studies have suggested that their function is largely unique. Although these receptors have been studied in detail for more than a decade, little data exist concerning the mechanisms by which these two proteins regulate distinct sets of genes. Using the TGFβ-inducible early gene-1 (TIEG) as a model, we demonstrate that TIEG is rapidly induced in response to estrogen in osteoblasts by ERβ, but not ERα. We have identified the regulatory elements utilized by ERβ and have demonstrated that ERβ recruits steroid receptor coactivator (SRC)1 and SRC2 to this regulatory region. Additionally, deletion of the ERβ-activation function 1 (AF1) domain drastically decreases the estrogen induction of TIEG. Through the use of chimeric receptors, we have demonstrated that the AF1 domain of ERβ is responsible for recruiting SRC1 and SRC2 and inducing the expression of TIEG in osteoblasts. Finally, SRC1, but not SRC2, is essential for TIEG induction by ERβ. Overall, these data demonstrate that the estrogen induction of TIEG is ERβ specific and that the AF1 domain of ERβ confers this specificity. Finally, a novel and important role for ERβ's AF1 is implicated in the recruitment of specific coactivators, suggesting that the AF1 may play a significant role in conferring the differences in regulation of gene expression by these two receptors.",
author = "Hawse, {John R} and Malayannan Subramaniam and Monroe, {David G} and Hemmingsen, {Amanda H.} and Ingle, {James N.} and Sundeep Khosla and Oursler, {Merry Jo} and Spelsberg, {Thomas C.}",
year = "2008",
month = "7",
doi = "10.1210/me.2007-0253",
language = "English (US)",
volume = "22",
pages = "1579--1595",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "7",

}

TY - JOUR

T1 - Estrogen receptor β isoform-specific induction of transforming growth factor β-inducible early gene-1 in human osteoblast cells

T2 - An essential role for the activation function 1 domain

AU - Hawse, John R

AU - Subramaniam, Malayannan

AU - Monroe, David G

AU - Hemmingsen, Amanda H.

AU - Ingle, James N.

AU - Khosla, Sundeep

AU - Oursler, Merry Jo

AU - Spelsberg, Thomas C.

PY - 2008/7

Y1 - 2008/7

N2 - The estrogen receptors (ER) α and β are important ligand-mediated transcription factors known to play significant biological roles in numerous tissues including bone. Despite the high homology shared by these receptors, recent studies have suggested that their function is largely unique. Although these receptors have been studied in detail for more than a decade, little data exist concerning the mechanisms by which these two proteins regulate distinct sets of genes. Using the TGFβ-inducible early gene-1 (TIEG) as a model, we demonstrate that TIEG is rapidly induced in response to estrogen in osteoblasts by ERβ, but not ERα. We have identified the regulatory elements utilized by ERβ and have demonstrated that ERβ recruits steroid receptor coactivator (SRC)1 and SRC2 to this regulatory region. Additionally, deletion of the ERβ-activation function 1 (AF1) domain drastically decreases the estrogen induction of TIEG. Through the use of chimeric receptors, we have demonstrated that the AF1 domain of ERβ is responsible for recruiting SRC1 and SRC2 and inducing the expression of TIEG in osteoblasts. Finally, SRC1, but not SRC2, is essential for TIEG induction by ERβ. Overall, these data demonstrate that the estrogen induction of TIEG is ERβ specific and that the AF1 domain of ERβ confers this specificity. Finally, a novel and important role for ERβ's AF1 is implicated in the recruitment of specific coactivators, suggesting that the AF1 may play a significant role in conferring the differences in regulation of gene expression by these two receptors.

AB - The estrogen receptors (ER) α and β are important ligand-mediated transcription factors known to play significant biological roles in numerous tissues including bone. Despite the high homology shared by these receptors, recent studies have suggested that their function is largely unique. Although these receptors have been studied in detail for more than a decade, little data exist concerning the mechanisms by which these two proteins regulate distinct sets of genes. Using the TGFβ-inducible early gene-1 (TIEG) as a model, we demonstrate that TIEG is rapidly induced in response to estrogen in osteoblasts by ERβ, but not ERα. We have identified the regulatory elements utilized by ERβ and have demonstrated that ERβ recruits steroid receptor coactivator (SRC)1 and SRC2 to this regulatory region. Additionally, deletion of the ERβ-activation function 1 (AF1) domain drastically decreases the estrogen induction of TIEG. Through the use of chimeric receptors, we have demonstrated that the AF1 domain of ERβ is responsible for recruiting SRC1 and SRC2 and inducing the expression of TIEG in osteoblasts. Finally, SRC1, but not SRC2, is essential for TIEG induction by ERβ. Overall, these data demonstrate that the estrogen induction of TIEG is ERβ specific and that the AF1 domain of ERβ confers this specificity. Finally, a novel and important role for ERβ's AF1 is implicated in the recruitment of specific coactivators, suggesting that the AF1 may play a significant role in conferring the differences in regulation of gene expression by these two receptors.

UR - http://www.scopus.com/inward/record.url?scp=46349084348&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=46349084348&partnerID=8YFLogxK

U2 - 10.1210/me.2007-0253

DO - 10.1210/me.2007-0253

M3 - Article

C2 - 18483178

AN - SCOPUS:46349084348

VL - 22

SP - 1579

EP - 1595

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 7

ER -