Receptors steroid hormone

Understanding of the intracellular localization of steroid receptors has gone through a number of phases, beginning with the view that receptors translocated from cytoplasm to nucleus in the presence of hormone. Indeed, with the exception of thyroid hormone receptors, which are exclusively nuclear in location, cell fractionation studies have revealed that in the absence of hormone, steroid receptors are extracted in the soluble or cytosolic fraction. However, when steroid is present in the cell, many occupied receptors are retained by purified cell nuclei. Histological procedures, such as immunocytochemistry, have confirmed the largely nuclear localization of occupied receptors, but... 

Sex steroid receptors are members of the steroid hormone receptor (SHR) family that ligand-dependently regulate functions of the sexual organs. Sex steroid receptors are the androgen receptor [1] (AR), the estrogen receptor a [2] and (3 [3] (ERa, ER 3), and the progesterone receptor [4] (PR). 

Steroid receptors belong to the nuclear receptor superfamily and bind steroid hormones. They are cytoplasmic when inactive and associated with chaperones. 

Coactivators enhancing the transcriptional activity of steroid hormone receptors activators include SRC-1 (steroid-receptor co-activator 1) or TEF2 (transcriptional intermediary factor 2), which are recruited by the DNA/ steroid hormone receptor complex. Their main role is to attract other transcriptional coactivators with histone acetyltransferase activity in order to decondense chromatin and allow for the binding of components of the general transcription apparatus. 

A comparison of several different steroid receptors with thyroid hormone receptors revealed a remarkable conservation of the amino acid sequence in certain regions, particularly in the DNA-binding domains. This led to the realization that receptors of the steroid or thyroid type are members of a large superfamily of nuclear receptors. Many related members of this family have no known ligand at present and thus are called orphan receptors. The nuclear receptor superfamily plays a critical role in the regulation of gene transcription by hormones, as described in Chapter 43. 

Steroid hormone receptors are phosphoproteins that have a DNA-binding domain and a steroid-binding domain. All steroid receptors have a molecular weight of 55,000-120,000. The state of phosphorylation appears to influence functional activity. 

Fig. 1.1. General mechanism of action of steroid hormones. Steroid hormones cross through the plasmatic membrane without apparent difficulty favored by gradient. Some, which can be considered prohormones, are metabolized and transformed into more active products. This is the case with testosterone, which becomes dihydrotestosterone (DHT) in the target tissues of androgens, through the 5-alfa-reductase enzyme. The hormone binds to the receptor, a soluble protein of the cellular cytosol that, in the absence of hormone, is found associated with other proteins (hsp90 and others) that maintain the receptor in an inactive state. The hormone-receptor bond causes the other proteins to separate and a homodimer to be formed. The homodimer is the activated form of the receptor since it is capable of recognizing the genes that depend on that steroid hormone as well as of activating its expression, which leads to the synthesis of specific proteins...

Like all steroids, aldosterone enters the target cell and combines with cytosolic mineralocorticoid receptor. Such receptors are not entirely specific for aldosterone and will also bind cortisol, the principal glucocorticoid hormone. The receptors are protected from cortisol activation by 11 3 hydroxysteroid dehydrogenase which... 

Specific transcription factors bind to enhancer regions or, in a few cases, to silencers and mod-ciate the formation of the initiation complex, thus regulating the rate of initiation of transcription. Each gene contains a variety of enhancer or silencer sequences in its regulatory region. The exact combination of specific transcription factors available (and active) in a particular cell at a particular time determines which genes will be transcribed at what rates, because specific transcription factors are proteins, their expression can be cell-type specific.. Additionally, hormones may regulate the activity of some specific transcription factors. Examples include steroid receptors and the CREB protein. 

In addition to the receptors mentioned in A, the family of steroid receptors also includes the product of the oncogene erb-A (see p. 398), the receptor for the environmental toxin dioxin, and other proteins for which a distinct hormone ligand has not been identified (known as orphan receptors ). Several steroid receptors—e. g., the retinoic acid receptor-form functional heterodimers with orphan receptors. 

The first crystal structure of the LED of the AR in complex with metri-bolone (R1881) was solved by Matias and colleagues in 2000 [38]. The LED has a similar three-dimensional structure to the other agonist-bound steroid receptors, namely the ERa, ERj6 and the PR [38]. The fact that all steroid hormone receptors bind similar hormone response elements (HREs) stands in sharp contrast to the specific activities elicited by application of the steroid... 

Examples of co-activators are the steroid receptor co-activator (SRC) family [48] and the components of the mammalian mediator complex, which possesses chromatin remodelling ability and tethers activated steroid hormone receptors to the basal transcription machinery [49]. Additional co-... 

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