Androgen receptor



The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of is_associated_with::nuclear receptor that is activated by binding either of the is_associated_with::androgenic hormones, is_associated_with::testosterone, or is_associated_with::dihydrotestosterone in the cytoplasm and then translocating into the nucleus. The androgen receptor is most closely related to the is_associated_with::progesterone receptor, and is_associated_with::progestins in higher dosages can block the androgen receptor.

The main function of the androgen receptor is as a DNA-binding is_associated_with::transcription factor that regulates gene expression; however, the androgen receptor has other functions as well. Androgen regulated genes are critical for the development and maintenance of the male sexual is_associated_with::phenotype.

Effect on development
In some cell types, testosterone interacts directly with androgen receptors, whereas, in others, testosterone is converted by 5-alpha-reductase to dihydrotestosterone, an even more potent is_associated_with::agonist for androgen receptor activation. Testosterone appears to be the primary androgen receptor-activating hormone in the is_associated_with::Wolffian duct, whereas dihydrotestosterone is the main androgenic hormone in the is_associated_with::urogenital sinus, is_associated_with::urogenital tubercle, and is_associated_with::hair follicles. Hence, testosterone is responsible primarily for the development of male primary sexual characteristics, whereas dihydrotestosterone is responsible for secondary male characteristics.

Androgens cause slow is_associated_with::epiphysis, or maturation of the bones, but more of the potent is_associated_with::epiphysis effect comes from the estrogen produced by is_associated_with::aromatization of androgens. Steroid users of teen age may find that their growth had been stunted by androgen and/or estrogen excess. People with too little sex hormones can be short during puberty but end up taller as adults as in is_associated_with::androgen insensitivity syndrome or is_associated_with::estrogen insensitivity syndrome.

Also, AR is_associated_with::knockout-mice studies have shown that AR is essential for normal female fertility, being required for development and full functionality of the is_associated_with::ovarian follicles and ovulation, working through both intra-ovarian and neuroendocrine mechanisms.

Maintenance of male skeletal integrity
Via the Androgen receptor, androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling can be attributed to both osteoblasts and osteocytes.

Genomic
The primary mechanism of action for androgen receptors is direct regulation of gene transcription. The binding of an is_associated_with::androgen to the androgen receptor results in a conformational change in the receptor that, in turn, causes dissociation of is_associated_with::heat shock proteins, transport from the is_associated_with::cytosol into the is_associated_with::cell nucleus, and dimerization. The androgen receptor dimer binds to a specific sequence of is_associated_with::DNA known as a is_associated_with::hormone response element. Androgen receptors interact with other proteins in the nucleus, resulting in up- or down-regulation of specific is_associated_with::gene transcription. Up-regulation or activation of transcription results in increased synthesis of is_associated_with::messenger RNA, which, in turn, is translated by is_associated_with::ribosomes to produce specific proteins. One of the known target genes of androgen receptor activation is the insulin-like growth factor I receptor (is_associated_with::IGF-1R). Thus, changes in levels of specific proteins in cells is one way that androgen receptors control cell behavior.

One function of androgen receptor that is independent of direct binding to its target DNA sequence, is facilitated by recruitment via other DNA-binding proteins. One example is is_associated_with::serum response factor, a protein that activates several genes that cause muscle growth.

Androgen receptor is modified by acetylation, which directly promotes contact independent growth of prostate cancer cells.

Non-genomic
More recently, androgen receptors have been shown to have a second mode of action. As has been also found for other steroid hormone receptors such as is_associated_with::estrogen receptors, androgen receptors can have actions that are independent of their interactions with DNA. Androgen receptors interact with certain is_associated_with::signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of changes in gene transcription, such as changes in ion transport. Regulation of signal transduction pathways by cytoplasmic androgen receptors can indirectly lead to changes in gene transcription, for example, by leading to phosphorylation of other transcription factors.

Gene
In humans, the androgen receptor is encoded by the AR is_associated_with::gene located on the is_associated_with::X chromosome at Xq11-12.

AR deficiencies
The is_associated_with::androgen insensitivity syndrome, formerly known as testicular feminization, is caused by a mutation of the androgen receptor gene located on the X chromosome (locus:Xq11-Xq12). The androgen receptor seems to affect neuron physiology and is defective in is_associated_with::Kennedy's disease. In addition, point mutations and trinucleotide repeat polymorphisms has been linked to a number of additional disorders.

Isoforms
Two isoforms of the androgen receptor (A and B) have been identified:
 * AR-A -  87 kDa - N-terminus truncated (lacks the first 187 amino acids), which results from in vitro proteolysis.
 * AR-B - 110 kDa - full length

Domains
Like other nuclear receptors, the androgen receptor is modular in structure and is composed of the following functional domains labeled A through F:
 * A/B) - N-terminal regulatory domain contains:
 * activation function 1 (AF-1) between residues 101 and 370 required for full ligand activated transcriptional activity
 * activation function 5 (AF-5) between residues 360-485 is responsible for the constitutive activity (activity without bound ligand)
 * dimerization surface involving residues 1-36 (containing the FXXLF motif where F = is_associated_with::phenylalanine, L = is_associated_with::leucine, and X = any amino acid residue) and 370-494, both of which interact with the LBD in an intramolecular   head-to-tail interaction
 * C) - is_associated_with::DNA binding domain (DBD)
 * D) - Hinge region - flexible region that connects the DBD with the LBD; along with the DBD, contains a ligand dependent is_associated_with::nuclear localization signal
 * E) - is_associated_with::Ligand binding domain (LBD) containing
 * activation function 2 (AF-2), responsible for agonist induced activity (activity in the presence of bound agonist)
 * AF-2 binds either the N-terminal FXXFL motif is_associated_with::intramolecularly or coactivator proteins (containing the LXXLL or preferably FXXFL motifs)
 * A ligand dependent is_associated_with::nuclear export signal
 * F) - C-terminal domain

Interactions
Androgen receptor has been shown to interact with:


 * is_associated_with::AKT1,
 * is_associated_with::BAG1,
 * is_associated_with::Beta-catenin,
 * is_associated_with::BRCA1,
 * is_associated_with::C-jun,
 * is_associated_with::Calmodulin 1,
 * is_associated_with::Caveolin 1,
 * is_associated_with::CDK9,
 * is_associated_with::COX5B,
 * is_associated_with::CREB-binding protein,
 * is_associated_with::Cyclin D1,
 * is_associated_with::Cyclin-dependent kinase 7,
 * is_associated_with::DACH1,
 * is_associated_with::Death associated protein 6,
 * is_associated_with::L-DOPA,
 * is_associated_with::EFCAB6,
 * is_associated_with::Epidermal growth factor receptor,
 * is_associated_with::FOXO1,
 * GAPDH,
 * is_associated_with::Gelsolin,
 * is_associated_with::GNB2L1,
 * is_associated_with::GSK3B,
 * is_associated_with::HDAC1,
 * HSP90AA1,
 * is_associated_with::HTATIP,
 * is_associated_with::MAGEA11,
 * is_associated_with::MED1,
 * is_associated_with::MYST2,
 * NCOA1,
 * NCOA2,
 * NCOA3,
 * is_associated_with::NCOA4,
 * is_associated_with::NCOA6,
 * NCOR2,
 * is_associated_with::NONO,
 * p300,
 * is_associated_with::PA2G4,
 * is_associated_with::PAK6,
 * is_associated_with::PATZ1,
 * PIAS2,
 * is_associated_with::PRPF6,
 * PTEN,
 * is_associated_with::RAD9A,
 * is_associated_with::RANBP9,
 * is_associated_with::RCHY1,
 * is_associated_with::Retinoblastoma protein,
 * is_associated_with::RNF14,
 * is_associated_with::RNF4,
 * is_associated_with::SART3,
 * is_associated_with::SIRT1,
 * SMAD3,
 * is_associated_with::Small heterodimer partner,
 * Src,
 * is_associated_with::SRY,
 * is_associated_with::STAT3,
 * is_associated_with::SVIL,
 * is_associated_with::Testicular receptor 2,
 * is_associated_with::Testicular receptor 4,
 * is_associated_with::TGFB1I1,
 * is_associated_with::TMF1,
 * is_associated_with::TRIM68,
 * is_associated_with::UBE2I,
 * is_associated_with::UXT, and
 * is_associated_with::ZMIZ1.