Biochemical mechanism and ultrastructure of human androgen receptor and its gene

Steroid hormones, such as androgens, exert profound effects on differentiation, development and growth in higher eukaryotes through interaction with specific intracellular receptors. Androgen receptors bind testosterone/dihydrotestosterone, and regulate genes necessary for male sexual differentiation and development. In subjects with a 46 XY karyotype, defects in the androgen receptor gene may result in a spectrum of developmental abnormalities ranging from a phenotypic female to varying degrees of incomplete masculinization. At puberty, androgens stimulate further growth and functional differentiation of male reproductive tract. Maintenance of spermatogenesis, sperm maturation and accessory sex gland function depend on androgens and their receptor. Human prostate cancers often remain androgen dependent in early stages. Steroid, act through a common biochemical pathway; entering cells by simple diffusion to bind to intracellular receptors. Steroid binding triggers an allosteric change transformation, causing the receptor to acquire high affinity for DNA. Transformed hormone-receptor complex regulates gene transcription as a trans-acting factor which binds to specific DNA elements, ''hormone-response elements''. The precise molecular mechanisms of transcriptional enhancement are unknown. The androgen receptor member of steroid receptors family, is part of a larger family of nuclear receptor proteins which include receptors for thyroid hormone and retinoic acid. Insight into the functional arrangement of the steroid receptors has come from the recent cloning and characterization of the various members of the human steroid receptor family. These include the glucocorticoid, estrogen, progesterone, mineralocorticoid, vitamin D and androgen receptors. The high degree of conservation in both nucleotide and amino acid sequence among these receptors suggested that certain regions perform important functions, such as DNA- and steroid-binding, that are common to all of these receptors. The human androgen receptor gene locus is near q12 on the long-arm of the X-chromosome. The coding region consists of eight exons with an open reading frame of 2757 nucleotide base pairs. The predominant mRNA transcript is 10-11 kilobases in length and the translated peptide consists of 919 amino acids with calculated molecular weight of 98,999. Exons 2 and 3 encode a span of 66 amino acids containing the putative DNA-binding domain organized into a structure consistent with two cysteine tetrahedral zinc-binding fingers proposed for other eukaryotic transcription factors. The 3' region from amino acid 676 in exon 4 amino acid residue 919 of exon 8, enocde the steroid-binding domain. The DNA- and steroid-binding domains of the human androgen receptor demonstrat 100% amino acid homology with the rat androgen receptor. Furthermore, the extraordinally high sequence homology among the human androgen, progesterone, mineralocorticoid and glucocorticoid receptors suggest that this group diverged from a common predecessor gene at a different time than did the estrogen and vitamin D receptors. Other studies have suggested that regulatory sequences for gene transcription may be contained within the N-terminal regional occupied by exon 1, as well as a portion of the steroid-binding domain. The future availability of androgen receptor antibody and DNA probes will make possible, new approaches for detecting defects in the human androgen receptor gene and for defining structure/function relationships of the receptor protein.