Diverse roles of androgen receptor (AR) domains in AR-mediated signaling

Abstract

Androgens control male sexual development and maintenance of the adult male phenotype. They have very divergent effects on their target organs like the reproductive organs, muscle, bone, brain and skin. This is explained in part by the fact that different cell types respond differently to androgen stimulus, even when all these responses are mediated by the same intracellular androgen receptor. To understand these tissue- and cell-specific readouts of androgens, we have to learn the many different steps in the transcription activation mechanisms of the androgen receptor (NR3C4). Like all nuclear receptors, the steroid receptors have a central DNA-binding domain connected to a ligand-binding domain by a hinge region. In addition, all steroid receptors have a relatively large amino-terminal domain. Despite the overall structural homology with other nuclear receptors, the androgen receptor has several specific characteristics which will be discussed here. This receptor can bind two types of androgen response elements (AREs): one type being similar to the classical GRE/PRE-type elements, the other type being the more divergent and more selective AREs. The hormone-binding domain has low intrinsic transactivation properties, a feature that correlates with the low affinity of this domain for the canonical LxxLL-bearing coactivators. For the androgen receptor, transcriptional activation involves the alternative recruitment of coactivators to different regions in the amino-terminal domain, as well as the hinge region. Finally, a very strong ligand-induced interaction between the amino-terminal domain and the ligand-binding domain of the androgen receptor seems to be involved in many aspects of its function as a transcription factor. This review describes the current knowledge on the structure-function relationships within the domains of the androgen receptor and tries to integrate the involvement of different domains, subdomains and motifs in the functioning of this receptor as a transcription factor with tissue- and cell-specific readouts.

Selective Roles for cAMP Response Element-binding Protein Binding Protein and p300 Protein as Coregulators for Androgen-regulated Gene Expression in Advanced Prostate Cancer Cells

“…Upon binding of the ligand, the AR translocates to the nucleus where it binds directly to DNA sequences known as androgen-responsive elements (AREs), which serve as regulatory (enhancer and silencer) elements for associated genes (1,2). The DNA-bound AR recruits coregulators (coactivators and/or corepressors) that remodel chromatin conformation around the ARE and the associated transcription start site (TSS) and regulate the assembly or disassembly of an active transcription complex on the TSS.…”

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

“…(1,2) Androgens act through their androgen receptor (AR), which is a ligand-dependent transcription factor. (3) Evidence for a direct role of AR in male skeletal homeostasis is derived from observations in genetically engineered ubiquitous AR knockout (ARKO) mice and orchidectomized (ORX) male mice. (4) Bone resorption is increased in ARKO and ORX males compared with wild-type (WT) mice, thereby reducing trabecular and cortical bone mass.…”

Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor

“…A ndrogen receptor (AR) contains an N-terminal transactivation domain (encoded by exon 1), the DNA binding domain (exons 2 and 3), a short hinge region (exon 4), and the C-terminal ligand binding domain (LBD; exons [4][5][6][7][8] where the androgenic ligands testosterone and dihydrotestosterone bind (1). When bound by androgens, AR undergoes a conformational change that permits nuclear translocation, DNA binding, and regulation of AR target genes (2).…”