Cytosol steroid receptor

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

Stimulation of C.P450 synthesis occurs at the transcriptional level, and different cytosolic receptors have been identified for benzpyrene, dioxin, isosafrole and 3-methylcholanthrene. The analogy with the mcxle of action of steroid hormones is striking. It must be remembered, however, that the existence of cytosolic steroid receptors in vivo is doubted [J.Gors-ki etal. Molec. Cell Endocrinol 36 (1984) 11-15]. Cytosolic receptors are probably artifacts of cell disruption, and steroid receptors are thought to reside only in the nucleus This may also apply to cytosolic receptors of C.P450 substrates [S.K.Yang etal. Science 196 (1977) 1199-1201, D.PfeU J.Friedrich Pharmazie 46 (1985) 217-221, J.Friedrich D.Pfeil... 

Steroid hormones act in a different manner from most hormones we have considered. In many cases, they do not bind to plasma membrane receptors, but rather pass easily across the plasma membrane. Steroids may bind directly to receptors in the nucleus or may bind to cytosolic steroid hormone receptors, which then enter the nucleus. In the nucleus, the hormone-receptor complex binds directly to specific nucleotide sequences in DNA, increasing transcription of DNA to RNA (Chapters 31 and 34). 

Carilla E, Briley M, Fauran F, et al. Binding of Permixon, a new treatment for prostatic benign hyperplasia, to the cytosolic androgen receptor in the rat prostate. J Steroid Biochem 20 521-523, 1984. 

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... 

Estradiol. The first neuroactive steroid receptor type to be recognized was that for estradiol [3]. In vivo uptake of [3H] estradiol, and binding to cell nuclei isolated from hypothalamus, pituitary and other brain regions, revealed steroid specificity closely resembling that of the uterus, where steroid receptors were first discovered [3]. Cytosolic estrogen receptors isolated from pituitary and brain tissue closely resemble those found in uterus and mammary tissue. A hallmark of the estrogen receptor is its existence... 

Meyers CY, Kolb VM, Gass GH, et al. 1988. Doisynolic-type acids - uterotropically potent estrogens which compete poorly with estradiol for cytosolic estradiol receptors. J Steroid Biochem 31 (4A) 393-404. 

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... 

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. 

Cytosolic Hormone Receptors. Steroid hormones typically bind to protein receptors, which are located directly within the cytosol (see Fig. 28-2).17 Of course, this means that the hormone must first enter the cell, which is easily accomplished by the steroid hormones because they are highly lipid soluble. After entering the cell, the hormone initiates a series of events that are depicted in Figure 28-3. Basically, the hormone and receptor form a large activated steroid-receptor complex.17 This complex travels to the cell s nucleus, where it binds to specific genes located within the DNA sequence.31,40 This process initiates gene expres-... 

FIGURE 28-3 Sequence of events of steroid hormone action. [1] Steroid hormone enters the cell, binds to a oytosolio receptor, and creates an activated steroid-receptor complex CS-FT). C2] S-R complex travels to the cell s nucleus, where it binds to specific gene segments on nuclear chromatin. [3] DNA undergoes transcription into messenger RNA (mRNA) units. (4) mRNA undergoes translation in the cytosol into specific proteins that alter cell function. 

Fig. 1. Intracellular events involved in steroid hormone action. A. Model in which the receptor is cytosolic and transfers tothe nucleus after binding with steroid (S). The cytosolic 8S receptor consists of a ligand binding unit ( ) and other units, one of which is a 90 kDa heat shock protein ( ). Activation is shown here as involving dimerisation of the ligand binding unit. This simplification of the true events applies to oestradiol receptor but not necessarily for other receptor classes. There is no agreement as to where activation occurs. B. Model in which unliganded receptor (0) is in the nucleus. A conformational change occurs on binding steroid (S) which may result in increased affinity for specific DNA sequences.

Table 11.1 Agonists and antagonists of cytosolic steroid hormone receptors...

Perhaps the environmental chemical most studied with regard to effects on the immune system has been 2,3,7,8-tetrachlorodibenzo-p-dioxin, which is also known as TCDD or dioxin . While it appears that dioxin may affect multiple cell types, it is apparent that the B cell is an especially sensitive target. The mechanism of action for the immunotoxic effects of dioxin remains poorly understood. It is well established that many of the actions of dioxin, including inhibition of the primary antibody response, are mediated by a specific cytosolic receptor, termed the aryl hydrocarbon receptor (AhR). AhR exhibits a profile of activity similar to steroid receptors in that the ligand-activated receptor undergoes a nuclear... 

Borg, A., Lennerstrand, J., Stenmark-Askmalm, M., Femo, M., Brisfors, A., Ohrvik, A., Stal, O., Killander, D., Lane, D., and Brundell, J. (1995) Prognostic significance of p53 overexpression in primary breast cancer a novel luminometric immunoassay applicable on steroid receptor cytosols. Br. J. Cancer 71,1013-1017. 

Simple alkyl esters also proved virtually inactive. Consequently, the 17/3-chloromethyl ester was held constant and 17a-carbonates with different substituents on the steroid skeleton were varied for further investigation. Loteprednol etabonate, and some of the other soft steroids, provided a significant improvement of the therapeutic index determined as the ratio between the anti-inflammatory activity and the thymus involution activity (114, 117,118). Furthermore, binding studies using rat lung cytosolic corticosteroid receptors showed that some of the compounds approach and even exceed the binding affinity of the most potent corticosteroids known. 

Cre function can also be regulated on a post-transcriptional level. If the cre recom-binase is fused with a mutated hormone binding domain of a steroid receptor, the fusion protein is sequestered into the cytosol and cannot reach the nucleus [20]. Only in the presence of a specific steroid binding to the hormone binding domain can the fusion protein translocate to the nucleus, where it will catalyze the DNA deletion. 

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