001   Factors that Mediate and Modulate Androgen Action

MJ McPhaul and M Young, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX

Androgens mediate a wide range of processes during embryogenesis and in the adult. In mammals, although a number of steroids can be shown to exert androgenic effects using in vitro and in vivo assays, testosterone and its 5a reduced metabolite, 5a-dihydrotestosterone (DHT) are considered to represent the principal androgens in mammals. Furthermore, although the effects that androgens exert differ widely between different tissues and cell types, genetic and biochemical data suggest that these effects are mediated via the protein products of a single androgen receptor gene, which is encoded on the X-chromosome. The last decade has witnessed an explosion of information regarding the manner in which steroid hormones modulate gene expression. At present, a body of increasingly detailed information is available as to the mechanisms by which nuclear receptors, such as the androgen receptor, regulate the activity of target genes. The studies have demonstrated the participation of a number of ancillary proteins in modulating the activation or repression by nuclear receptors. These proteins have been shown to possess a variety of activities, including the capacity to modify chromatin structure. In parallel to experiments focused on the mechanism by which nuclear receptors regulate the transcription of responsive genes, experiments have demonstrated the importance of androgen metabolism in specific cell types. A number of enzymes capable of catalyzing the inactivation or synthesis of active androgens have been described. The complement of activities expressed in an individual tissue or cell type is likely to affect the degree of androgen - responsiveness. The results of such investigations provide a perspective on the number of levels of complexity by which differential gene regulation by androgens may occur in different cell types. Such insights may provide avenues by which to modulate the actions of androgens selectively in specific tissues.