Molecular mechanisms of estrogen action in target tissues

Abstract

The majority of signals that govern cell operations have their origin in theplasma membrane. They proceed from membrane receptors that respond tosubstances of diverse origins. An important part of these signals arrives at thecells via blood circulation, as it is the case of endocrine signals transmitted byhormones. Another essential group of signals originates in the neighborhoodof the cells, or even in the cell itself. This is the case of paracrine and autocrinesignals transmitted by an extensive assemblage of growth and differentiationfactors.The interaction of external signals with membrane receptors generates secondmessengers. These messengers either modify the cell concentration ofions or metabolites or alter the functional state of a chain of several moleculesthat act as intermediaries. These intermediaries may modify the intensity ofdetermined biochemical reactions or, in other cases, are integrated into themachinery of gene transcription and alter the expression of specific genes. Theconsequences of these activities can lead to the induction of cell division.An important group of endocrine signals does not requiremembrane receptors,second messengers, or intermediaries in signaling chains. They proceedfrom substances that seem to penetrate into the interior of cells without difficulty,where they join with intracellular receptors, and through which they acton the cell genome. These substances are small liposoluble molecules, of whichseveral are of a hormonal nature: the steroid hormones - androgens, estrogens,progestagens, glucocorticoids, andmineral corticoids - the thyroid hormones,and vitamin D3. There are also nonhormonal substances, such as retinoic acid,prostaglandin J2, or fatty acids, which utilize intracellular receptors and exertpowerful genomic effects. All these substances share common mechanisms ofaction through soluble intracellular proteins that are members of the nuclearhormone receptor family (Evans 1988; Vaseduvan et al. 2002).Once nuclear hormone receptors are bound to their hormone, they arecapable of being integrated directly into themachinery that regulates the transcriptionof specific genes. This action is more direct, and apparently moreprimitive, than that originating in membrane receptors. By controlling geneexpression, the hormones regulate more the abundance of determinate, specificproteins rather than their biochemical activity. Those hormone-receptorcomplexes are also efficient regulators of cell proliferation.Nuclearhormone receptors accumulate several functions ina single molecule.They are capable of recognizing and binding small molecules like steroids withhigh affinity and specificity. These hormone-receptor complexes are capableof recognizing and joining with specific sequences of DNA present only ingenes that are the object of hormonal regulation. They are capable, in short,of interacting with other proteins - coactivators or corepressors - that participatein the regulation of the machinery of gene transcription and of initiatingor modifying the expression of specific genes. The meeting of all these functions,and others not mentioned, in a single molecule make these receptors anextremely elaborate product from the point of view of evolution.This chapter reviews the main characteristics of two of the better knownmembers of the nuclear hormone receptor family: estrogen receptors ? and ?(ER? andER?). First, the different functional regions harbored by themoleculeof the receptor are described. These properties will be used to describe thecellular, molecular, and other consequences that derive from the interactionsof receptors with their own hormone, other proteins, or DNA.The interaction of estrogen receptorswith signaling systems of the cellmembranethat respond to growth factors and mediate nongenomic, fast actions ofestrogens will be reviewed as well. These mechanisms have a growing importancein the comprehension of phenomena like the induction of endothelialNOS (nitric oxide synthase) by estrogens (Rubanyi et al. 2002).