Molecular mechanisms of androgen and antiandrogen action
The steroid hormones testosterone and 5a-dihydrotestosterone (androgens) control the development, differentiation and function of male reproductive and accessory sex tissues, such as seminal vesicle, epididymis and prostate. Changes in cell properties induced by androgens require the presence of a specific cellular receptor, the androgen receptor (AR). The AR is a member of the subfamily of intracellular receptors (Evans, 1988) which also include the progesterone receptor (PR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and estrogen receptor (ER). The cellular concentration of these receptors is extremely low, under normal physiological conditions rarely exceeding 0.01% of total cellular protein (McDonnell et aI., 1987). As a result, it was only with the cloning of the receptor cDNAs and subsequent genetic analysis that a clearer understanding of structure-function relationships of the receptor proteins has emerged. The cDNAs for all of the known steroid hormone receptors have been cloned and sequenced. A comparison of their deduced amino acid sequences reveals regions of extensive homology indicating that they belong to a family of closely related proteins. Functional mapping of the intracellular receptors indicates that the most highly conserved region comprises the DNA binding domain, whereas the carboxyl terminus contains sequences required for hormone binding, dimerization, nuclear localization, interaction with heat-shock proteins, and transcription regulation. The N-terminal domains of the receptor proteins are mainly involved in transcription regulation (Beato, 1989; Tsai and O'Malley, 1994; Beato et aI., 1995). The steroid hormone receptors are latent transcription factors which are activated upon interaction with their specific ligands. The mechanism by which the AR and other steroid hormone receptors mediate their biological effects in target cells is comparable. In the absence of hormone, the latent receptor resides in a large macromolecular complex comprising heat shock protein 90 (hsp90), hsp70, the immunophilin p59 and other proteins (Smith and Toft, 1993). Binding of the respective ligand triggers a complex set of interactions of the receptor with chromatin and with a variety of other proteins, finally leading to modifications in the pattern of gene expression and cell fate (Fig. 1.1). Inhibition of biological action of steroid hormones can be obtained by two major routes: first, by occupation of the receptor with an antagonist instead of an agonist (steroid receptor antagonists), or second, by prevention of formation of the agonist in the biological system. Formation of agonists can be prevented through excision of hormone-producing organs (e.g. castration) or by blockade of hormone biosynthesis. Although substances inhibiting biosynthetic pathways are also often called antagonists, this type of antagonists is not the subject of this thesis.
|Keywords||androgen receptor, antiandrogens, endocrinology|
|Promotor||Grootegoed, J.A. (Johan)|
|Publisher||Erasmus MC: University Medical Center Rotterdam|
Kuil, C.W.. (1997, January 29). Molecular mechanisms of androgen and antiandrogen action. Erasmus MC: University Medical Center Rotterdam. Retrieved from http://hdl.handle.net/1765/17820