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. 2006;7(8):497-508.
doi: 10.2174/138920206779315737.

Estrogen signaling multiple pathways to impact gene transcription

Maria Marino  1 , Paola Galluzzo, Paolo Ascenzi
Affiliations

Estrogen signaling multiple pathways to impact gene transcription

Maria Marino et al. Curr Genomics. 2006.

Abstract

Steroid hormones exert profound effects on cell growth, development, differentiation, and homeostasis. Their effects are mediated through specific intracellular steroid receptors that act via multiple mechanisms. Among others, the action mechanism starting upon 17beta-estradiol (E2) binds to its receptors (ER) is considered a paradigmatic example of how steroid hormones function. Ligand-activated ER dimerizes and translocates in the nucleus where it recognizes specific hormone response elements located in or near promoter DNA regions of target genes. Behind the classical genomic mechanism shared with other steroid hormones, E2 also modulates gene expression by a second indirect mechanism that involves the interaction of ER with other transcription factors which, in turn, bind their cognate DNA elements. In this case, ER modulates the activities of transcription factors such as the activator protein (AP)-1, nuclear factor-kappaB (NF-kappaB) and stimulating protein-1 (Sp-1), by stabilizing DNA-protein complexes and/or recruiting co-activators. In addition, E2 binding to ER may also exert rapid actions that start with the activation of a variety of signal transduction pathways (e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The debate about the contribution of different ER-mediated signaling pathways to coordinate the expression of specific sets of genes is still open. This review will focus on the recent knowledge about the mechanism by which ERs regulate the expression of target genes and the emerging field of integration of membrane and nuclear receptor signaling, giving examples of the ways by which the genomic and non-genomic actions of ERs on target genes converge.

Keywords: Estrogen; estrogen receptors; gene transcription; genomic and non-genomic action mechanism.

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Figures

Fig. (1)
Fig. (1)
Domain organization of human ERαand ERβ (A). ERs consist of the N- terminal region involved in transactivation (A/B domains, AF-1), the DNA binding domain (DBD, C domain), the hinge region involved in dimerization (D domain), the C-terminal region containing ligand binding domain (LBD, E/F domain, AF-2) and transactivation function-2 (AF-2). The percentage indicates the homology between ERα and ERβ. (B) Binding mode of ERE to dimeric ERα (PDB ID:1HCQ) [163]. Spheres indicate the zinc atoms. For details, see text.
Fig. (2)
Fig. (2)
Schematic model illustrating the relationship between rapid, intermediate, and long term actions of E2 on target cells. Palmitoyla-tion (PA) allows the estrogen receptor (ER) localization at the plasma membrane. 17β -estradiol (E2) binding induces ER relocalization, association to signaling proteins, and triggers the activation of signaling cascades. The kinase activations phosphory-late ER, modulate transcriptional coactivators recruitment, and enhance AP-1 and Sp-1 activation. After dimerization ERs directly interact with ERE on DNA. ERs-DNA indirect association occurs through protein-protein interactions with the Sp-1 and AP-1 transcription factors. AP-1, activating protein-1; MNAR, modulator of non-genomic activity of ERα ; PA, palmitic acid; Sp-1, stimulating factor-1. For details, see text.
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