INTRODUCTION

Nuclear receptors (NR) are a superfamily of ligand activated transcription factors that modulate specific gene expression. Currently there are over 100 nuclear receptors identified. They are categorized into steroid receptor subfamies: Class I NR -classically defined as ligand dependent and will homodimerize, Class II NR -classically defined as ligand independent with potential for both homo- and heterodimerization, and Orphan receptors -ligands only recently being characterized.

In the classical model of estrogen receptor activation, estrogen receptor (ER) is classified as a Class I nuclear receptor. Only through interaction with estrogen and estrogen like molecules does ER exert its diverse array of biological effects. In the absence of estrogen, ER is sequestered within nuclei of target cells and maintained in an inactive state by association with heat-shock proteins. Binding of estrogen or similar ligand induces a conformational change in ER, an event that promotes ER homodimerization and high-affinity binding of ER to specific sites on DNA- estrogen response elements (EREs). Once bound to DNA, the estrogen-receptor complex regulates the expression of estrogen-responsive genes.

Two Isoforms of ER

The depth and complexity of ER activation has since expanded. For many years, it was believed that estrogen exerted it effects through a single receptor, now referred to as ER-a. More recently, a second estrogen receptor, ER-b, was identified. The two receptors share common structural and functional domains , bind to estrogen with high affinity, and bind estrogen response elements in a similar manner. But as suggested by the differences in structure, ER-a and ER-b are found to differ in many ways with respect to tissue distribution, transcriptional activities, and phenotypes in knockout models.

ERa (NCBI-OMIM)- Mapped to the long arm of chromosome 6. 595 amino acids with a N-terminal modulating domain, central DNA-binding domain (DBD) and a C-terminal ligand-binding domain (LBD).
ERb (NCBI-OMIM)- Mapped to band q22-24 of chromosome 14. Slightly shorter than the classical ERa with 530 amino acids. Contains all the same functional domain except that ER-b lacks a portion of the C-terminal domain which is important for the effects for certain anti-estrogens. The regions of highest homology between the two receptors are the DBD (>95%) and the LBD (>55%).

Mechanisms of ER Signaling

It is now known that ERa and ERb not only homodimerize but can also heterodimerize. In addition, new mechansims for ER activation have been delineated which adds to the complexity of estrogen receptor signal transduction.

• Hormone dependent phosphorylation is suspected to be an important aspect of ER binding to specific response elements.
• Estrogen receptor subtypes can regulate transcription through AP-1 response elements through direct interaction with AP-1 transcription factors c-fos and c-jun.
• Cross talk between different signaling pathways can also induce ER activation. Receptor tyrosine kinases and IGF receptors can indirectly activate ER through direct phosphorylation of specific residues.
• Conformational changes in ER structure, determined by specific ligand binding, expose different amino acids that are critical for binding to protein factors involved in targeted transcriptional activation.
• Finally, ER alone does not direct gene expression. Cellular pools of co-regulatory proteins play an integral role as signaling intermediates in enhancing or repressing transcriptional activity. Generally, co-activators have intrinsic histone acetylation activity associated with increased transcriptional activity and co-repressors possess deacetylase activity which repress gene activity by keeping chromatin in a more condensed state.
  
  

(OMIM, Online Mendelian Inheritance in Man, will give you detailed textual information and references on either receptors. NCBI-Entrez)

References:

Klinge CM. Estrogen receptor interaction with co-activators and co-repressors. Steroids. 2000 May;65(5):227-51.Review.
Enmark E, Gustafsson JA. Oestrogen receptors - an overview. J Intern Med. 1999 Aug;246(2):133-8. Review.
Osborne CK, Zhao H, Fuqua SA. Selective estrogen receptor modulators: structure, function, and clinical use.
J Clin Oncol. 2000 Sep;18(17):3172-86. Review.

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