Zhong Xun Zhou

The Androgen Receptor: An Overview

Publisher Summary This chapter provides an overview of the androgen receptor (AR). AR is a ligand-activated transcriptional regulatory protein that mediates androgen-induced male sexual development and function. The chapter presents a schematic diagram that highlights the major functional domains of human AR. The centrally located DNA-binding domain contains nine highly conserved Cys residues common to the family of steroid receptors. This arrangement of Cys residues led to the confirmation of the requirement for zinc in the tertiary structure of this region of steroid receptors. It was recently noted that the AR protein is significantly stabilized by androgen binding. Pulse-chase experiments using 35S-labeled AR in transiently transfected monkey kidney COS cells showed rapid degradation of receptor in the absence of androgen (t1/2 = 1 hour at 37°C) or in the presence of nonandrogenic hormones. Androgen addition increased the AR protein half-life to 6 hours at 37°C. The sixfold androgen-induced stabilization of AR protein contrasts androgen-induced down-regulation of AR mRNA in tissues of the male reproductive tract.

Partial androgen insensitivity with phenotypic variation caused by androgen receptor mutations that disrupt activation function 2 and the NH2- and carboxyl-terminal interaction

Partial androgen insensitivity with sex phenotype variation in two unrelated families was associated with missense mutations in the androgen receptor (AR) gene that disrupted the AR NH(2)-terminal/carboxy terminal interaction. Each mutation caused a single amino acid change within the region of the ligand-binding domain that forms activation function 2 (AF2). In one family, the mutation I737T was in alpha helix 4 and in the other F725L was between helices 3 and 4. Neither mutation altered androgen binding as determined by assays of mutant AR in the patients cultured genital skin fibroblasts or of recombinant mutant receptors transfected into COS cells. In transient cotransfection assays in CV1 cells, transactivation with the AR mutants at low concentrations of DHT was reduced several fold compared with wild-type AR but increased at higher concentrations. Defects in NH(2)-terminal/carboxy terminal interactions were identified in mammalian two hybrid assays. In similar assays, there was reduced binding of the p160 coactivators TIF2/SRC2 and SRC1 to the mutant AR ligand binding domains (LBD). In the family with AR I737T, sex phenotype varied from severely defective masculinization in the proband to a maternal great uncle whose only manifestation of AIS was severe gynecomastia. He was fertile and passed the mutation to two daughters. The proband of the F725L family was also incompletely masculinized but was raised as a male while his half-sibling by a different father was affected more severely and reared as a female. These studies indicate that the function of an AR AF2 mutant in male development can vary greatly depending on the genetic background.