Steroid response element

An account of the principles which help to understand how hormones achieve their roles in the body is given in Chapter 12. The understanding is based on separation of the effects of hormones into three components the action, the effects (biochemical and physiological) and the function. A steroid hormone binds to a cytosolic intracellular receptor, which then moves into the nucleus where it binds to DNA at a specific site (the steroid response element) and activates genes which result in the formation of proteins that elicit biochemical and physiological effects. This is discussed for cortisol in Chapter 12 and aldosterone in Chapter 22. Much of the interest in the reproductive steroid hormones is in the physiological effects and how these account for their functions. 

Situations occur in which receptors are present in cells which are hormone insensitive. This is relatively common in tumour cells where our ignorance as to the molecular mechanisms involved are covered by the use of the term post receptor defect [27,28]. In at least one such case, this defect lies within the steroid response element of the gene [28]. This regulatory region usually, but not always, found 5 to the RNA initiation site, is the DNA acceptor site(s) for the steroid receptor complex (Fig. 4). It has the properties of an enhancer (see other articles for more com-... 

Fig. 4. Specificity determined by availability of receptor binding regions of DNA. With an oestrogen (E) sensitive gene, the receptor complex binds to specific regions of DNA (steroid response element) which influences the efficiency of mRNA initiation. If the response element is blocked, the gene is unresponsive to the steroid.

Another level of sensitivity might also be determined by the steroid response element. Thus far, virtually all discussions on agonists/antagonists have centred on... 

Fig. 5. Specificity of steroid response element. A. In this example (mouse mammary tumour virus), the element will bind receptors for glucocorticoids (G), androgen (A), progestin (P) and mineralocorticoid (M) so that each of these classes of steroid stimulate transcription. This type of specificity can vary from cell to cell possibly due to other protein factors (not shown). B. Although oestrogen (E) receptor will not act as an agonist for mouse mammary tumour virus transcription, it may antagonise the agonist activity of glucocorticoids (G).

Steroid hormones perform many functions in cells, one of which is to activate gene expression by binding to steroid receptors, proteins in the cytoplasm that, when activated, act as factors that initiate transcription. All steroid hormones are derived from cholesterol and, as a result, have similar chemical structures. Steroid hormones differ one from another primarily in hydrox-ylation of particular carbon atoms and by aromatiza-tion of the steroid A ring of the molecule. Once a steroid hormone binds to a steroid receptor protein, the complex undergoes a series of structural changes that result in the complex binding to DNA at a particular sequence called a steroid response element (SRE)... 

Steroid receptors are an exception to the general rule that receptors are memhrane proteins. Steroid receptors are normally present as soluble proteins in the cytoplasm. Steroids diffuse across the hydrophobic cell membrane and bind to their specific receptors. The receptors then translocate to the nucleus by simple diffusion, where they act as transcription factors by binding to specific regions of chromosomal DNA (steroid response elements), thus controlling transcription of particular genes. 

Hormone response elements (for steroids, T3, retinoic acid, peptides, etc) act as—or in conjunction with— enhancers or silencers (Chapter 43). Other processes that enhance or silence gene expression—such as the response to heat shock, heavy metals (Cd and Zn +), and some toxic chemicals (eg, dioxin)—are mediated through specific regulatory elements. Tissue-specific expression of genes (eg, the albumin gene in liver, the hemoglobin gene in reticulocytes) is also mediated by specific DNA sequences. 

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors the retinoic acid receptors (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

Navarro D, Ledn L, Chirino R, Fernandez L, Pestano J, Dlaz-Chico BN (1998) The two native estrogen receptor forms of 8S and 4S present in cytosol from human uterine tissues display opposite reactivity with tamoxifen aziridine and the estrogen response element. J Steroid Biochem Mol Biol 64 49... 

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