Androgen Receptor

Introduction

The androgen receptor (AR) is part of the steroid hormone receptor family of molecules, which also includes the progesterone, estrogen, mineralocorticoid, retinoic acid, thyroid, and vitamin D receptors. The AR is a transcription factor, primarily responsible for mediating the physiologic effects of androgens through binding of the androgen–AR complex to specific DNA target sequences and inducing or suppressing the transcription of target genes.

Androgen receptor structure and function

The AR gene is a single-copy gene located on chromosome Xq11.2-q12. The gene spans approximately 90 kb of DNA, and is oriented with the 5’ end toward the centromere. The coding sequence is made up of eight exons that code for a 10.6 kb mRNA forming a 2757-base pair open reading frame. The AR ( Figure 3.1 ), like all steroid receptors, contains three regions: (1) a ligand-binding domain (LBD), (2) a DNA-binding domain (DBD), and (3) a transactivation domain. The first exon codes for the entire N-terminal domain (NTD), which is the transcriptional regulatory region of the protein. This transactivation domain contains a polyglutamine sequence of variable length, which is encoded by a CAG triplet repeat sequence. This CAG sequence begins at codon 58 and extends for 11–31 (average 21) repeats in normal men. The variable nature of this polyglutamine sequence is thought to be due to slipping of the DNA polymerase during DNA replication. While some studies suggest that CAG repeat length is inversely associated with prostate cancer (PCa) risk, this concept still remains controversial. Long CAG repeat length (40–62 repeats) is seen in Kennedy’s disease, an inherited neuromuscular degenerative disease.

The second and third exons encode the DBD, which is a highly conserved region among steroid hormone receptors. The DBD is composed of two zinc finger motifs. The first zinc finger is encoded by exon 2 and confers receptor-specificity for androgen-response elements (AREs); the second zinc finger is encoded by exon 3 and is involved in the dimerization of the receptor and its binding to the major groove of DNA. Finally, exons 4–8 code for the C-terminal LBD, which is significantly variable among steroid hormone receptors. The LBD folds into a ligand-binding pocket composed of 12 helices, which encloses bound ligand and induces structural change in the receptor allowing for coactivator binding. A hinge region connects the DBD and LBD, and contains a nuclear localization signal.

Mechanism of Action

The inactive AR resides in the cytoplasm, bound to chaperones. AR activation proceeds in multiple steps beginning with initial complex formation with certain chaperonins, binding of ligand, posttranslational modifications, and dimerization ( Figure 3.2 ). The receptor complex translocates into the nucleus and forms transcriptional coactivator complexes that remodel chromatin in order to access the target initiation site. Finally, the complex acts to stabilize the RNA polymerase II machinery for repeated rounds of transcription.