Transcriptional activation of genes by 17β-estradiol through estrogen receptor-Sp1 interactions

doi:10.1016/S0083-6729(01)62006-5

Vitamins & Hormones

Volume 62, 2001, Pages 231-252

https://doi.org/10.1016/S0083-6729(01)62006-5 Get rights and content

Abstract

Estrogen receptor-α (ERα) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. The classic mechanism of (ERα) action is associated with estrogen-induced formation of a nuclear (ERα) homodimer, binding to 5′-regulatory estrogen response elements (EREs) in target gene promoters, interaction with other nuclear proteins, and general transcription factors to activate gene expression. (ERα) also interacts with Sp1 protein to transactivate genes through binding Sp1(N)_xERE or Sp1(N)_xERE half-site ( $12$ ) motifs where both (ERα) and Sp1 bind DNA elements. Activation through Sp1 $(N)_{x} ERE 12$ requires interactions of both proteins with their cognate DNA elements as well as additional nuclear factors to form a functional ERα/Sp1-DNA complex. Recent studies also show that (ERα) and Sp1 physically interact and (ERα) preferentially binds to the C-terminal DNA-binding domain of Sp1 protein. Moreover, ERα/Sp1 can activate transcription from a consensus GC-rich Sp1 binding site in transient transfection studies in MCF-7 human breast cancer cells, and this response is also observed with ERα variants that do not contain the DNA-binding domain. Several genes that are induced by estrogens in MCF-7 cells are activated through one or more GC-rich sites in their regulatory regions and these include the cathepsin D, E2F1, bcl-2, c-fos, adenosine deaminase, insulinlike growth factor binding protein 4, and retinoic acid receptor α1 genes. ERα/Sp1 and ERβ/Sp1 action is dependent on ligand structure and cell context and ERβ/Sp1 is primarily associated with decreased ligand-dependent gene expression. ERα/Sp1, like ERα/AP1, represents a pathway for hormone activation of genes in which the receptor does not bind DNA, and results of ongoing studies suggest that ERα/Sp1 plays an important role in transcriptional activation of multiple growth regulatory genes in breast cancer cells.

References (110)

M. Beato et al.
Steroid hormone receptors: Many actors in search of a plot
Cell
(1995)
F. Borellini et al.
Induction of Sp1-p53 DNA-binding heterocomplexes during granulocyte/macrophage colony-stimulating factor-dependent proliferation in human erythroleukemia cell line. TF-1
J. Biol. Chem.
(1993)
B. Cenni et al.
Ligand-independent activation of steroid receptors: New roles for old players
Trends Endocrinol. Metab.
(1999)
H.T. Cohen et al.
An important von Hippel-Lindau tumor suppressor domain mediates Sp1-binding and self-association
Biochem. Biophys. Res. Commun.
(1999)
S.M. Cowley et al.
Estrogen receptors α and β form heterodimers on DNA
J. Biol. Chem.
(1997)
J. Dennig et al.
Members of the Sp transcription factor family control transcription from the uteroglobin promoter
J. Biol. Chem.
(1995)
H. Ding et al.
Functional interactions between Sp1 or Sp3 and the helicase-like transcription factor mediate basal expression from the human plasminogen activator inhibitor-1 gene
J. Biol. Chem.
(1999)
L. Dong et al.
Mechanisms of transcriptional activation of bcl-2, gene expression by 17β-estradiol in breast cancer cells
J. Biol. Chem.
(1999)
D. El-Ashry et al.
Estrogen induction of TGF-α is mediated by an estrogen response element composed of two imperfect palindromes
J. Steroid Biochem. Mol. Biol.
(1996)
C.K. Glass et al.
Nuclear receptor coactivators
Curr. Opin. Cell Biol.
(1997)

S.M. Hyder et al.

Interaction of human estrogen receptors alpha and beta with the same naturally occurring estrogen response elements

Biochem. Pharmacol.

(1999)

D. Kardassis et al.

c-Jun transactivates the promoter of the human p21^WAF1/Cip1 gene by acting as a superactivator of the ubiquitous transcription factor Sp1

J. Biol. Chem.

(1999)

S.A. Kliewer et al.

An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway

Cell

(1998)

A. Kobayashi et al.

Cooperative interaction between AhR. Arnt and Sp1 for the drug-inducible expression of CYP1A1 gene

J. Biol. Chem.

(1996)

D. Krainc et al.

Synergistic activation of the N-methyl-d-aspartate receptor subunit 1 promoter by myocyte enhancer factor 2C and Sp1

J. Biol. Chem.

(1998)

V. Krishnan et al.

Estrogen receptor-Sp1 complexes mediate estrogen-induced cathepsin D gene expression in MCF-7 human breast cancer cells

J. Biol. Chem.

(1994)

R. Kumar et al.

The structure of the nuclear hormone receptors

Steroids

(1999)

R. Li et al.

Direct interaction between Sp1 and the BPV enhancer E2 protein mediates synergistic activation of transcription

Cell

(1991)

D.J. Mangelsdorf et al.

The nuclear receptor superfamily: The second decade

Cell

(1995)

N.J. McKenna et al.

Nuclear receptor coactivators: Multiple enzymes, multiple complexes, multiple functions

J. Steroid Biochem. Mol. Biol.

(1999)

D. Monte et al.

Regulation of the human P450scc gene by steroidogenic factor 1 is mediated by CBP/p300

J. Biol. Chem.

(1998)

G.I. Owen et al.

Progesterone regulates transcription of the p21^WAF1 cyclin-dependent kinase inhibitor gene through Sp1 and CBP/p300

J. Biol. Chem.

(1998)

T. Perlmann et al.

Nuclear receptors in Sicily: All in the famiglia

Cancer Res. Cell

(1997)

K. Roder et al.

Interaction between the two ubiquitously expressed transcription factors NF-Y and Sp1

Gene

(1999)

O. Rohr et al.

COUP-TF and Sp1 interact and cooperate in the transcriptional activation of the human immunodeficiency virus type 1 long terminal repeat in human microglial cells

J. Biol. Chem.

(1997)

H.B. Sanchez et al.

Cooperation by sterol regulatory element-binding protein and Sp1 in sterol regulation of low density lipoprotein receptor gene

J. Biol. Chem.

(1995)

B. Saville et al.

Ligand-, cell- and estrogen receptor subtype $(α β)- dependent$ activation at GC-rich (Sp1) promoter elements

J. Biol. Chem.

(2000)

A. Scholz et al.

Hormone-induced recruitment of Sp1 mediates estrogen activation of the rabbit uteroglobin gene in endometrial epithelium

J. Biol. Chem.

(1998)

J.W. Schwabe et al.

The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: How receptors discriminate between their response elements

Cell

(1993)

Y. Suzuki et al.

Physical interactions between retinoic acid receptor and Spl: Mechanism for induction of urokinase by retinoic acid

Blood

(1999)

D. Tasset et al.

Distinct classes of transcriptional activating domains function by different mechanisms

Cell

(1990)

T. Barkhem et al.

Differential response of estrogen receptor α and estrogen receptor β to partial estrogen agonists/antagonists

Mol. Pharmacol.

(1998)

S.E. Bates et al.

Expression of transforming growth factor-α and its messenger ribonucleic acid in human breast cancer: Its regulation by estrogen and its possible functional significance

Mol. Endocrinol.

(1988)

S.R. Batistuzzo de Medeiros et al.

Functional interactions between the estrogen receptor and the transcription activator Sp1 regulate the estrogen-dependent transcriptional activity of the vitellogenin A1 io promoter

J. Biol. Chem.

(1997)

E. Biesiada et al.

Myogenic basic helixloop-helix proteins and Sp1 interact as components of a multiprotein transcriptional complex required for activity of the human cardiac α-actin promoter

Mol. Cell Biol.

(1999)

B. Blumberg et al.

SXR, a novel steroid and xenobiotic-sensing nuclear receptor

Genes Dev.

(1998)

P.S. Cooke et al.

Mechanism of estrogen action: Lessons from the estrogen receptor-α knockout mouse

Biol. Reprod.

(1998)

J.F. Couse et al.

Prevention of the polycystic ovarian phenotype and characterization of ovulatory capacity in the estrogen receptor-α knockout mouse

Endocrinology

(1999)

J.F. Couse et al.

Estrogen receptor null mice: What have we learned and where will they lead us?

Endocr. Rev.

(1999)

J.F. Couse et al.

Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene

Mol. Endocrinol.

(1995)

P.S. Danielian et al.

Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors

EMBO J.

(1992)

A. Doetzlhofer et al.

Histone deacetylase 1 can repress transcription by binding to Sp1

Mol. Cell Biol.

(1999)

R. Duan et al.

Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: Role of estrogen receptor Sp1 complex formation

Endocrinology

(1998)

D. Dubik et al.

Mechanism of estrogen activation of c-myc Onogene expression

Oncogene

(1992)

D.P Edwards

Coregulatory proteins in nuclear hormone receptor action

Vitam. Horm.

(1999)

A. Emili et al.

Species-specific interaction of the glutamine-rich activation domains of Sp1 with the TATA box-binding protein

Mol. Cell Biol.

(1994)

H. Endoh et al.

Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor α

Mol. Cell. Biol.

(1999)

E. Enmark et al.

Orphan nuclear receptors—The first eight years

Mol. Endocrinol.

(1996)

E. Enmark et al.

Human estrogen receptor β-gene structure, chromosomal localization, and expression pattern

J. Clin. Endocrinol. Metab.

(1997)

K.B. Horwitz et al.

Nuclear receptor coactivators corepressors

Mol. Endocrinol.

(1996)

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Transcriptional activation of genes by 17β-estradiol through estrogen receptor-Sp1 interactions

Abstract

Cell

J. Biol. Chem.

Trends Endocrinol. Metab.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

Curr. Opin. Cell Biol.

Biochem. Pharmacol.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Steroids

Cell

Cell

J. Steroid Biochem. Mol. Biol.

J. Biol. Chem.

J. Biol. Chem.

Cancer Res. Cell

Gene

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Blood

Cell

Differential response of estrogen receptor α and estrogen receptor β to partial estrogen agonists/antagonists

Mol. Pharmacol.

Expression of transforming growth factor-α and its messenger ribonucleic acid in human breast cancer: Its regulation by estrogen and its possible functional significance

Mol. Endocrinol.

Functional interactions between the estrogen receptor and the transcription activator Sp1 regulate the estrogen-dependent transcriptional activity of the vitellogenin A1 io promoter

J. Biol. Chem.

Myogenic basic helixloop-helix proteins and Sp1 interact as components of a multiprotein transcriptional complex required for activity of the human cardiac α-actin promoter

Mol. Cell Biol.

SXR, a novel steroid and xenobiotic-sensing nuclear receptor

Genes Dev.

Mechanism of estrogen action: Lessons from the estrogen receptor-α knockout mouse

Biol. Reprod.

Prevention of the polycystic ovarian phenotype and characterization of ovulatory capacity in the estrogen receptor-α knockout mouse

Endocrinology

Estrogen receptor null mice: What have we learned and where will they lead us?

Endocr. Rev.

Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene

Mol. Endocrinol.

Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors

EMBO J.

Histone deacetylase 1 can repress transcription by binding to Sp1

Mol. Cell Biol.

Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: Role of estrogen receptor Sp1 complex formation

Endocrinology

Mechanism of estrogen activation of c-myc Onogene expression

Oncogene

Coregulatory proteins in nuclear hormone receptor action

Vitam. Horm.

Species-specific interaction of the glutamine-rich activation domains of Sp1 with the TATA box-binding protein

Mol. Cell Biol.

Purification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor α

Mol. Cell. Biol.

Orphan nuclear receptors—The first eight years

Mol. Endocrinol.

Human estrogen receptor β-gene structure, chromosomal localization, and expression pattern

J. Clin. Endocrinol. Metab.

Nuclear receptor coactivators corepressors

Mol. Endocrinol.