Androgens in Health and Disease.pdf - E Library

Chapter 9/Androgen Signaling in Prostatic Neoplasia and Hyperplasia 159
Fig. 1. Mechanism of AR action. Testosterone is the main androgen in circulation. Once inside
the cell, T can be 5α-reduced into DHT by the enzyme 5α-reductase. Both T and DHT can bind
AR, but DHT binds with greater affinity. Upon ligand binding, the receptor dissociates from heat
shock proteins and undergoes a conformational change, phosphorylation, dimerization, and
nuclear translocation. Eventually the AR–ligand complex binds DNA and interacts with a number
of coactivators that function as docking molecules between the AR and the general transcription
apparatus (GTA). The AR functions as a transcription factor and interacts with response
elements located in the promoter region upstream of androgen-dependent genes to regulate their
transcription. The spectrum of biological activities regulated by AR includes male sexual differentiation,
development of the male sexual phenotype at puberty, and regulation of gonadotropin
secretion and maintenance of these effects after puberty. Abbreviations: ARE, androgen-responsive
element; DBD, DNA-binding domain; GTA, general transcription apparatus; LBD, ligandbinding
domain.
typical androgen target tissues, such as the central nervous system, and are associated
with an expansion of the polyQ tract located in the N-terminus. Characterization of AR
mutants has resulted in the identification of regions of the molecule that regulate additional
functions, including nuclear import (19), binding to the nuclear matrix (20), transcriptional
activation, dimerization, ligand binding, and DNA binding (21–25).
AR Coactivators
Although it was originally thought that steroid receptors interact directly through
transcriptional activation functions (TAF) with proteins in the general transcription complex
to stimulate transcription of target genes, studies in recent years have shown that
most of these functional interactions are mediated by proteins termed “coactivators.”