Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids

Stavroula Kousteni, Li Han, Jin Ran Chen, Maria Almeida, Lilian Plotkin, Teresita Bellido, Stavros C. Manolagas

Research output: Contribution to journalArticle

220 Citations (Scopus)

Abstract

It has been found that 4-estren-3α17β-diol, a synthetic ligand for the estrogen receptor (ER) or androgen receptor (AR), which does not affect classical transcription, reverses bone loss in ovariectomized females or orchidectomized males without affecting the uterus or seminal vesicles, demonstrating that the classical genotropic actions of sex steroid receptors are dispensable for their bone-protective effects, but indispensable for their effects on reproductive organs. We have now investigated the mechanism of action of this compound. We report that, identically to 17β-estradiol or dihydrotestosterone, but differently from raloxifene, estren alters the activity of Elk-1, CCAAT enhancer binding protein-β (C/EBPβ), and cyclic adenosine monophosphate-response element binding protein (CREB), or c-Jun/c-Fos by an extranuclear action of the ER or AR, resulting in activation of the Src/Shc/ERK pathway or downregulation of JNK, respectively. All of these effects are non-sex specific, require only the ligand-binding domain of the receptor, and are indispensable for the antiapoptotic action of these ligands on osteoblastic and HeLa cells. Moreover, administration of 17β-estradiol or 4-estren-3α,17β-diol to ovariectomized mice induces phosphorylation of ERKs, Elk-1, and C/EBPβ, downregulates c-Jun, and upregulates the expression of egr-1, an ERK/SRE target gene. Kinase-initiated regulation of commonly used transcription factors offers a molecular explanation for the profound skeletal effects of sex steroid receptor ligands, including synthetic ones that are devoid of classical transcriptional activity.

Original languageEnglish (US)
Pages (from-to)1651-1664
Number of pages14
JournalJournal of Clinical Investigation
Volume111
Issue number11
StatePublished - Jun 2003
Externally publishedYes

Fingerprint

Transcription Factors
Phosphotransferases
Steroids
CCAAT-Enhancer-Binding Proteins
Ligands
Bone and Bones
Steroid Receptors
Androgen Receptors
Estrogen Receptors
Estradiol
Down-Regulation
CREB-Binding Protein
Estradiol Congeners
MAP Kinase Signaling System
Seminal Vesicles
Dihydrotestosterone
Response Elements
HeLa Cells
Cyclic AMP
Reverse Transcription

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. / Kousteni, Stavroula; Han, Li; Chen, Jin Ran; Almeida, Maria; Plotkin, Lilian; Bellido, Teresita; Manolagas, Stavros C.

In: Journal of Clinical Investigation, Vol. 111, No. 11, 06.2003, p. 1651-1664.

Research output: Contribution to journalArticle

Kousteni, Stavroula ; Han, Li ; Chen, Jin Ran ; Almeida, Maria ; Plotkin, Lilian ; Bellido, Teresita ; Manolagas, Stavros C. / Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 11. pp. 1651-1664.
@article{cfadf04089f54374a5cf453a83115138,
title = "Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids",
abstract = "It has been found that 4-estren-3α17β-diol, a synthetic ligand for the estrogen receptor (ER) or androgen receptor (AR), which does not affect classical transcription, reverses bone loss in ovariectomized females or orchidectomized males without affecting the uterus or seminal vesicles, demonstrating that the classical genotropic actions of sex steroid receptors are dispensable for their bone-protective effects, but indispensable for their effects on reproductive organs. We have now investigated the mechanism of action of this compound. We report that, identically to 17β-estradiol or dihydrotestosterone, but differently from raloxifene, estren alters the activity of Elk-1, CCAAT enhancer binding protein-β (C/EBPβ), and cyclic adenosine monophosphate-response element binding protein (CREB), or c-Jun/c-Fos by an extranuclear action of the ER or AR, resulting in activation of the Src/Shc/ERK pathway or downregulation of JNK, respectively. All of these effects are non-sex specific, require only the ligand-binding domain of the receptor, and are indispensable for the antiapoptotic action of these ligands on osteoblastic and HeLa cells. Moreover, administration of 17β-estradiol or 4-estren-3α,17β-diol to ovariectomized mice induces phosphorylation of ERKs, Elk-1, and C/EBPβ, downregulates c-Jun, and upregulates the expression of egr-1, an ERK/SRE target gene. Kinase-initiated regulation of commonly used transcription factors offers a molecular explanation for the profound skeletal effects of sex steroid receptor ligands, including synthetic ones that are devoid of classical transcriptional activity.",
author = "Stavroula Kousteni and Li Han and Chen, {Jin Ran} and Maria Almeida and Lilian Plotkin and Teresita Bellido and Manolagas, {Stavros C.}",
year = "2003",
month = "6",
language = "English (US)",
volume = "111",
pages = "1651--1664",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",

}

TY - JOUR

T1 - Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids

AU - Kousteni, Stavroula

AU - Han, Li

AU - Chen, Jin Ran

AU - Almeida, Maria

AU - Plotkin, Lilian

AU - Bellido, Teresita

AU - Manolagas, Stavros C.

PY - 2003/6

Y1 - 2003/6

N2 - It has been found that 4-estren-3α17β-diol, a synthetic ligand for the estrogen receptor (ER) or androgen receptor (AR), which does not affect classical transcription, reverses bone loss in ovariectomized females or orchidectomized males without affecting the uterus or seminal vesicles, demonstrating that the classical genotropic actions of sex steroid receptors are dispensable for their bone-protective effects, but indispensable for their effects on reproductive organs. We have now investigated the mechanism of action of this compound. We report that, identically to 17β-estradiol or dihydrotestosterone, but differently from raloxifene, estren alters the activity of Elk-1, CCAAT enhancer binding protein-β (C/EBPβ), and cyclic adenosine monophosphate-response element binding protein (CREB), or c-Jun/c-Fos by an extranuclear action of the ER or AR, resulting in activation of the Src/Shc/ERK pathway or downregulation of JNK, respectively. All of these effects are non-sex specific, require only the ligand-binding domain of the receptor, and are indispensable for the antiapoptotic action of these ligands on osteoblastic and HeLa cells. Moreover, administration of 17β-estradiol or 4-estren-3α,17β-diol to ovariectomized mice induces phosphorylation of ERKs, Elk-1, and C/EBPβ, downregulates c-Jun, and upregulates the expression of egr-1, an ERK/SRE target gene. Kinase-initiated regulation of commonly used transcription factors offers a molecular explanation for the profound skeletal effects of sex steroid receptor ligands, including synthetic ones that are devoid of classical transcriptional activity.

AB - It has been found that 4-estren-3α17β-diol, a synthetic ligand for the estrogen receptor (ER) or androgen receptor (AR), which does not affect classical transcription, reverses bone loss in ovariectomized females or orchidectomized males without affecting the uterus or seminal vesicles, demonstrating that the classical genotropic actions of sex steroid receptors are dispensable for their bone-protective effects, but indispensable for their effects on reproductive organs. We have now investigated the mechanism of action of this compound. We report that, identically to 17β-estradiol or dihydrotestosterone, but differently from raloxifene, estren alters the activity of Elk-1, CCAAT enhancer binding protein-β (C/EBPβ), and cyclic adenosine monophosphate-response element binding protein (CREB), or c-Jun/c-Fos by an extranuclear action of the ER or AR, resulting in activation of the Src/Shc/ERK pathway or downregulation of JNK, respectively. All of these effects are non-sex specific, require only the ligand-binding domain of the receptor, and are indispensable for the antiapoptotic action of these ligands on osteoblastic and HeLa cells. Moreover, administration of 17β-estradiol or 4-estren-3α,17β-diol to ovariectomized mice induces phosphorylation of ERKs, Elk-1, and C/EBPβ, downregulates c-Jun, and upregulates the expression of egr-1, an ERK/SRE target gene. Kinase-initiated regulation of commonly used transcription factors offers a molecular explanation for the profound skeletal effects of sex steroid receptor ligands, including synthetic ones that are devoid of classical transcriptional activity.

UR - http://www.scopus.com/inward/record.url?scp=0038819062&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038819062&partnerID=8YFLogxK

M3 - Article

VL - 111

SP - 1651

EP - 1664

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 11

ER -