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Review
. 2008 Nov;41(5):263-75.
doi: 10.1677/JME-08-0103. Epub 2008 Sep 4.

Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways

Stephen Safe  1 , Kyounghyun Kim
Affiliations
Review

Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways

Stephen Safe et al. J Mol Endocrinol. 2008 Nov.

Erratum in

  • J Mol Endocrinol. 2009 Apr;42(4):359. Kim, Kyoungkim [corrected to Kim, Kyounghyun]

Abstract

17beta-estradiol binds to the estrogen receptor (ER) to activate gene expression or repression and this involves both genomic (nuclear) and non-genomic (extranuclear) pathways. Genomic pathways include the classical interactions of ligand-bound ER dimers with estrogen-responsive elements in target gene promoters. ER-dependent activation of gene expression also involves DNA-bound ER that subsequently interacts with other DNA-bound transcriptions factors and direct ER-transcription factor (protein-protein) interactions where ER does not bind promoter DNA. Ligand-induced activation of ER/specificity protein (Sp) and ER/activating protein-1 [(AP-1); consisting of jun/fos] complexes are important pathways for modulating expression of a large number of genes. This review summarizes some of the characteristics of ER/Sp- and ER/AP-1-mediated transactivation, which are dependent on ligand structure, cell context, ER-subtype (ERalpha and ERbeta), and Sp protein (SP1, SP3, and SP4) and demonstrates that this non-classical genomic pathway is also functional in vivo.

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Figures

Figure 1
Figure 1
A summary of E2-responsive genes containing functional GC-rich & ERE1/2 motifs. There is evidence that formation of this complex may contain other proteins.
Figure 2
Figure 2
Hormonal activation of cyclin D1, bcl-2, and c-Fos in breast cancer cells. In addition to GC-rich sites activated by ERα/Sp, E2-dependent activation of non-genomic cAMP/PKA (cyclin D1 and bcl-2) and MAPK/PI3K(c-Fos) pathways were also identified.
Figure 3
Figure 3
Multiple E2-responsive elements. The PADI4 and prolactin receptor genes contain E2-responsive GC-rich sites and other functional cis-element that contributed to E2-induced transactivation.
Figure 4
Figure 4
Different mechanisms of hormonal activation of E2F1 in MCF-7 cells and ZR-75 cells.
Figure 5
Figure 5
Mechanisms of E2-dependent downregulation and induction of VEGFR2 in MCF-7 and ZR-75 cells, respectively.
Figure 6
Figure 6
Wild-type and ERα variants and domains of ERα required for transactivation by E2 and structurally diverse estrogenic compounds in MCF-7 (—) and MDA-MB-231 (---) breast cancer cells.
Figure 7
Figure 7
Domains of ERα and ERβ required for ligand-dependent activation of ER/AP1 (i.e.deletion results in loss of activity) (104, 107) and comparisons with activation of ERα /Sp.
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