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Overview

Cellular signaling of estrogen is mediated through two estrogen receptors (ERs), ESR1 and ESR2. The first ER, now known as ESR1, was cloned in 1986. This receptor was regarded as the only ER that mediates estrogenic effects, until a second ER, now known as ESR2, was cloned from rat prostate. ESR1 and ESR2 belong to the superfamily of nuclear receptors and specifically to the family of steroid receptors that act as ligand-regulated transcription factors. ESR1 and ESR2 have a high sequence homology and share affinity for the same ligands and DNA response elements.

Binding of ligand activates ERs, by a mechanism that involves dissociation of heat shock proteins and dimerization of receptor proteins. Estrogen-modulated gene transcription is exerted via different mechanisms: the genomic and the nongenomic pathways. The canonical model for ER-mediated regulation of gene expression involves the direct binding of dimeric ER to DNA sequences known as estrogen response elements (EREs), followed by recruitment of a variety of coregulators to alter chromatin structure and facilitate recruitment of the RNA polymerase II (Pol II) transcriptional machinery.

The transcriptional activity of ERs can be modulated by different types of post-translational modifications such as phosphorylation, acetylation, sumoylation, ubiquitination and methylation.

ESR1 and ESR2 exhibit different affinities for some natural compounds, and distinct expression patterns in a variety of tissues. Transcriptional activation by ESR1 is mediated by two distinct activation functions: the constitutively active AF-1 and the ligand-dependent AF-2. ESR2 seems to have a weaker corresponding AF-1 function and thus depends more on the AF-2 for its transcriptional activation function. ESR1 and ESR2 have different activities in certain ligand, cell-type, and promoter contexts.

Figures
FIGURE 1 Schematic Illustration of ER Signaling Mechanisms (adapted from Bjomstrom and Sjoberg, 2005, PMID 15695368)
1. Classical mechanism of ER action. Nuclear E2-ERs bind directly to EREs in target gene promoters. 2. ERE-independent genomic actions. Nuclear E2-ER complexes are tethered through protein-protein interactions to a transcription factor complex (TF) that contacts the target gene promoter. 3. Ligand-independent genomic actions. Growth factors (GF) activate protein-kinase cascades, leading to phosphorylation (P) and activation of nuclear ERs at EREs. 4. Nongenomic actions. Membrane E2-ER complexes activate protein-kinase cascades, leading to altered functions of proteins in the cytoplasm, e.g. activation of eNOS, or to regulation of gene expression through phosphorylation (P) and activation of a TF.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.