Androgen receptor
Ensembl | |||||||||
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UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) |
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Location (UCSC) | Chr X: 67.54 – 67.73 Mb | Chr X: 97.19 – 97.37 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Androgen_recep | |||||||||
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Identifiers | |||||||||
Symbol | Androgen_recep | ||||||||
Pfam | PF02166 | ||||||||
InterPro | IPR001103 | ||||||||
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The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of
The main function of the androgen receptor is as a
Function
Effect on development
In some cell types, testosterone interacts directly with androgen receptors, whereas, in others, testosterone is converted by
Androgens cause slow maturation of the bones, but more of the potent maturation effect comes from the estrogen produced by 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 androgen insensitivity syndrome or estrogen insensitivity syndrome.[17]
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.[19]
Role in females
The AR plays a role in regulating female sexual, somatic, and behavioral functions. Experimental data using AR
Moreover, the importance of understanding female androgen receptors lies in their role in several genetic disorders including androgen insensitivity syndrome (AIS). Complete (CAIS) and partial (PAIS) which are a result of mutations in the genes that code for AR. These mutations cause the inactivation of AR due to mutations conferring resistance to circulating testosterone, with more than 400 different AR mutations reported.[citation needed]
Mechanism of action
Genomic
The primary mechanism of action for androgen receptors is
Androgens (also called androgenic hormones), such as testosterone or dihydrotestosterone, are understood to exert their primary effects through binding to an androgen receptor in the cytosol. The receptor is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via androgen responsive elements.[20] This androgen response mechanism is perhaps best known and characterized in the context of male sexual differentiation and puberty, but plays a role in a variety of tissue types and processes.[21][22] Upon binding to androgens, the androgen receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen-responsive genes.[23]
The binding of an androgen to the androgen receptor results in a
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 serum response factor, a protein that activates several genes that cause muscle growth.[27]
Androgen receptor is modified by post-translational modification through acetylation,[28] which directly promotes AR-mediated transactivation, apoptosis[29] and contact-independent growth of prostate cancer cells.[30] AR acetylation is induced by androgens[31] and determines recruitment into chromatin.[32] The AR acetylation site is a key target of NAD-dependent and TSA-dependent histone deacetylases[33] and long non-coding RNA.[34]
Non-genomic
More recently, androgen receptors have been shown to have a second mode of action. As has been also found for other
Genetics
Gene
In humans, the androgen receptor is encoded by the AR gene located on the X chromosome at Xq11–12.[36][37]
Deficiencies
At least 165 disease-causing mutations in this gene have been discovered.
CAG repeats
The AR gene contains
Mutations
The enhancer and the gene encoding for these receptors contain recurrent mutations, such as structural rearrangements and copy number changes, acquired in the progression of metastatic castration-resistant prostate cancer (mCRPC) treatment with therapy targeting these receptors (abiraterone, enzalutamide), make the disease progression determined by the androgen receptor genotype.[45]
Structure
Isoforms
Two isoforms of the androgen receptor (A and B) have been identified:[46]
- AR-A – 87 amino acids), which results from in vitro proteolysis.[47]
- 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
- A/B) – N-terminal regulatory domain contains:[49]
- 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 = phenylalanine, L = leucine, and X = any amino acid residue) and 370–494, both of which interact with the ligand binding domain (LBD) in an intramolecular[50][51][52] head-to-tail interaction[53][54][55]
- C) – DNA binding domain(DBD)
- D) – Hinge region; flexible region that connects the DBD with the LBD; along with the DBD, contains a ligand dependent nuclear localization signal[56]
- E) – 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 intramolecularly or coactivator proteins (containing the LXXLL or preferably FXXFL motifs)[55]
- A ligand dependent nuclear export signal[57]
- F) – C-terminaldomain
Splice variants
AR-V7 is an androgen receptor
Clinical significance
High expression in androgen receptor has been linked to aggression and sex drive by affecting the HPA and HPG axis[61]
Aberrant androgen receptor coregulator activity may contribute to the progression of prostate cancer.[62][45]
Ligands
Compound | RBA[b]
|
---|---|
Metribolone | 100 |
Dihydrotestosterone | 85 |
Cyproterone acetate | 7.8 |
Bicalutamide | 1.4 |
Nilutamide | 0.9 |
Hydroxyflutamide | 0.57 |
Flutamide | <0.0057 |
Notes:
|
Agonists
- Endogenous androgens (e.g., testosterone, dihydrotestosterone, androstenedione, androstenediol, dehydroepiandrosterone)
- Synthetic androgens (e.g., methyltestosterone, metandienone, nandrolone, trenbolone, oxandrolone, stanozolol)
Mixed
Antagonists
- Steroidal antiandrogens (e.g., cyproterone acetate, chlormadinone acetate, spironolactone, oxendolone)
- Nonsteroidal antiandrogens (e.g., flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, RU-58841)
- N-Terminal domain antiandrogens (e.g., bisphenol A, EPI-001, ralaniten, JN compounds)[64]
As a drug target
The AR is an important therapeutic target in
Drug resistance
Alteration of ARs may lead to treatment resistance (castration resistance) in prostate cancer as there may be
Interactions
Androgen receptor has been shown to
- AKT1,[67]
- BAG1,[68][69][70]
- BRCA1,[77][78]
- C-jun,[79]
- Calmodulin 1,[80]
- Caveolin 1,[81]
- CDK9,[82]
- COX5B,[83]
- CREB-binding protein,[84][85][86][87]
- Cyclin D1,[88][89][90][91]
- Cyclin-dependent kinase 7,[92]
- DACH1,[93]
- Death associated protein 6,[94]
- L-DOPA,[95]
- EFCAB6,[96]
- Epidermal growth factor receptor,[97][98]
- FOXO1,[99]
- GAPDH,[100]
- Gelsolin,[101]
- GNB2L1,[102]
- GSK3B,[103]
- HDAC1,[104]
- HSP90AA1,[105][106]
- HTATIP,[104]
- MAGEA11,[107][108]
- MED1,[109]
- MYST2,[110]
- NCOA1,[72][111][112]
- NCOA2,[71][86][107][113][114]
- NCOA3,[113][115][116]
- NCOA4,[67][114][117][118][119][120][121][122][123]
- NCOA6,[124]
- NCOR2,[71][125][126]
- NONO,[86]
- p300,[127]
- PA2G4,[128]
- PAK6,[129][130]
- PATZ1,[131]
- PIAS2,[132][133]
- PRPF6,[134]
- PTEN,[135]
- RAD9A,[136]
- RANBP9,[137]
- RCHY1,[138]
- Retinoblastoma protein,[139][140]
- RNF14,[114][117][141][142]
- RNF4,[131][143][144]
- SART3,[145]
- SIRT1,[33]
- SMAD3,[146][147][148]
- Small heterodimer partner,[149]
- SRY,[152]
- STAT3,[153][154]
- SVIL,[155]
- Testicular receptor 2,[156]
- Testicular receptor 4,[157]
- TGFB1I1,[117][158]
- TMF1,[159]
- TRIM68,[160]
- UBE2I,[71][72][161][162][163][164]
- UXT,[165] and
- ZMIZ1.[166]
See also
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External links
- GeneReviews/NCBI/NIH/UW entry on Androgen Insensitivity Syndrome
- OMIM entries on Androgen Insensitivity Syndrome
- GeneReviews/NIH/NCBI/UW entry on Spinal and Bulbar Muscular Atrophy, Kennedy's Disease, SBMA, X-Linked Spinal and Bulbar Muscular Atrophy
- OMIM entries on Spinal and Bulbar Muscular Atrophy, Kennedy's Disease, SBMA, X-Linked Spinal and Bulbar Muscular Atrophy
- Androgen+Receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Brinkmann AO. "Androgen physiology: receptor and metabolic disorders" (PDF). In Robert McLachlan (ed.). Endocrinology of Male Reproduction. Endotext.org. Archived from the original (PDF) on 2012-02-22. Retrieved 2008-04-29.
- Gottlieb B (2007-07-24). "The Androgen Receptor Gene Mutations Database Server". McGill University. Archived from the original on 22 April 2008. Retrieved 2008-04-29.
- Thompson J (2006-09-30). "Molecular Mechanisms of Androgen Receptor Interactions" (PDF). Helsinki University Biomedical Dissertations No. 80. University of Helsinki. Archived from the original (PDF) on 6 April 2008. Retrieved 2008-04-29.
- Human AR genome location and AR gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: P10275 (Human Androgen receptor) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: P19091 (Mouse Androgen receptor) at the PDBe-KB.