Wikipedia

Androgen receptor

Theandrogen receptor(AR), also known asNR3C4(nuclear receptor subfamily 3, group C, member 4), is a type ofnuclear receptor[9]that is activated by binding any of theandrogenichormones,includingtestosteroneanddihydrotestosterone,[10]in thecytoplasmand then translocating into thenucleus.The androgen receptor is most closely related to theprogesterone receptor,andprogestinsin higher dosages can block the androgen receptor.[11][12]

AR
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesAR,AIS, AR8, DHTR, HUMARA, HYSP1, KD, NR3C4, SBMA, SMAX1, TFM, androgen receptor
External IDsOMIM:313700;MGI:88064;HomoloGene:28;GeneCards:AR;OMA:AR - orthologs
Orthologs
SpeciesHumanMouse
Entrez

367

11835

Ensembl

ENSG00000169083

ENSMUSG00000046532

UniProt

P10275
Q9NUA2

P19091

RefSeq (mRNA)

NM_001011645
NM_000044
NM_001348061
NM_001348063
NM_001348064

NM_013476

RefSeq (protein)

NP_038504

Location (UCSC)Chr X: 67.54 – 67.73 MbChr X: 97.19 – 97.37 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Androgen_recep
crystal structure of the human androgen receptor ligand binding domain bound with an androgen receptor nh2-terminal peptide, ar20-30, and r1881
Identifiers
SymbolAndrogen_recep
PfamPF02166
InterProIPR001103
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary
Normal function of the androgen receptor. Testosterone (T) enters the cell and, if 5-alpha-reductase is present, is converted into dihydrotestosterone (DHT). Upon steroid binding, the androgen receptor (AR) undergoes a conformational change and releases heat-shock proteins (hsps). Phosphorylation (P) occurs before or after steroid binding. The AR translocates to the nucleus where dimerization, DNA binding, and the recruitment of coactivators occur. Target genes are transcribed (mRNA) and translated into proteins.[5][6][7][8]

The main function of the androgen receptor is as aDNA-bindingtranscription factorthatregulates gene expression;[13]however, the androgen receptor has other functions as well.[14]Androgen-regulated genes are critical for the development and maintenance of the male sexualphenotype.

Function

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Effect on development

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In some cell types, testosterone interacts directly with androgen receptors, whereas, in others, testosterone is converted by5-alpha-reductaseto dihydrotestosterone, an even more potentagonistfor androgen receptor activation.[15]Testosterone appears to be the primary androgen receptor-activating hormone in theWolffian duct,whereas dihydrotestosterone is the main androgenic hormone in theurogenital sinus,urogenital tubercle,andhair follicles.[16]Testosterone is therefore responsible primarily for the development of maleprimary sexual characteristics,whilst dihydrotestosterone is responsible forsecondary male characteristics.

Androgens cause slow maturation of the bones, but more of the potent maturation effect comes from theestrogenproduced byaromatizationof androgens.Steroidusers 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 inandrogen insensitivity syndromeorestrogen insensitivity syndrome.[17]

Knockout-micestudies have shown that the androgen receptor is essential for normal female fertility, being required for development and full functionality of theovarian folliclesandovulation,working through both intra-ovarian andneuroendocrinemechanisms.[18]

Maintenance of male skeletal integrity

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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 bothosteoblastsandosteocytes.[19]

Role in females

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The AR plays a role in regulating female sexual, somatic, and behavioral functions. Experimental data using ARknockoutfemale mice, provides evidence that the promotion of cardiac growth, kidney hypertrophy, cortical bone growth and regulation oftrabecularbone structure is a result of DNA-binding-dependent actions of the AR in females.

Moreover, the importance of understanding female androgen receptors lies in their role in several genetic disorders including androgen insensitivity syndrome (AIS).Complete(CAIS) andpartial(PAIS) which are a result ofmutationsin 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

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Genomic

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The primary mechanism of action for androgen receptors isdirect regulationofgene transcription.

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 aconformational changein the receptor that, in turn, causes dissociation ofheat shock proteins,transport from thecytosolinto thecell nucleus,anddimerization.The androgen receptor dimer binds to a specific sequence of DNA known as ahormone response element,where it forms macromolacular protein condensates that might facilitate rapid gene regulation as consequence of local high protein concentrations together with other coregulators.[24]Androgen receptors interact with other proteins in the nucleus, resulting in up- or down-regulation of specificgenetranscription.[25]Up-regulation or activation of transcription results in increased synthesis ofmessenger RNA,which, in turn, is translated byribosomesto produce specific proteins. One of the known target genes of androgen receptor activation is theinsulin-like growth factor 1 receptor(IGF-1R).[26]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 otherDNA-binding proteins.One example isserum response factor,a protein that activates several genes that cause muscle growth.[27]

Androgen receptor is modified bypost-translational modificationthroughacetylation,[28]which directly promotes AR-mediatedtransactivation,apoptosis[29]and contact-independent growth ofprostate cancercells.[30]AR acetylation is induced by androgens[31]and determines recruitment intochromatin.[32]The AR acetylation site is a key target ofNAD-dependent andTSA-dependenthistone deacetylases[33]andlong non-coding RNA.[34]

Non-genomic

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More recently, androgen receptors have been shown to have a second mode of action. As has been also found for othersteroid hormone receptorssuch asestrogen receptors,androgen receptors can have actions that are independent of their interactions with DNA.[14][35]Androgen receptors interact with certainsignal transductionproteins 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 inion 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.

Genetics

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Gene

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In humans, the androgen receptor is encoded by theARgenelocated on theX chromosomeat Xq11–12.[36][37]

Deficiencies

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At least 165 disease-causing mutations in this gene have been discovered.[38]Theandrogen insensitivity syndrome,formerly known as testicular feminization, is caused by a mutation in the androgen receptor gene on theX chromosome(locus: Xq11–Xq12).[39]The androgen receptor seems to affect neuron physiology and is defective inKennedy's disease.[40][41]In addition,point mutationsandtrinucleotide repeatpolymorphismshave been linked to a number of additional disorders.[42]

CAG repeats

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The AR gene containsCAG repeatsthat affect receptor function, where fewer repeats leads to increased receptor sensitivity to circulating androgens and more repeats leads to decreased receptor sensitivity. Studies have shown that racial variation in CAG repeats exists,[43][44]with African-Americans having fewer repeats than non-Hispanic white Americans.[43]The racial trends in CAG repeats parallels the incidence and mortality of prostate cancer in these two groups.

Mutations

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Theenhancerand 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

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Structure of full length human androgen receptor including N-terminal domain, DNA binding domain, and Ligand binding domain. Corresponding PDB file is available at Sheikhhassani et al.[46]
Structural domains of the two isoforms (AR-AandAR-B) of the human androgen receptor. Numbers above the bars refer to the amino acid residues that separate the domains starting from the N-terminus (left) to C-terminus (right). NTD = N-terminal domain, DBD = DNA-binding domain, LBD = ligand-binding domain, AF = activation function.

Isoforms

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Twoisoformsof the androgen receptor (AandB) have been identified:[47]

Domains

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Like other nuclear receptors, the androgen receptor is modular in structure and is composed of the following functionaldomainslabeledAthroughF:[49]

  • A/B) – N-terminal is a regulatory domain which is intrinsically disordered[50]and contains several key motifs/segments:[51]
    • Dimerization surface involving residues 1–36, the23FQNLF27motif[52](B only) nd 370–494, both of which interact with the ligand binding domain (LBD) in an intramolecular[53][54][55]head-to-tail interaction[56][57][58]
    • Polyglutamine repeat[59](AR-B only)
    • Transactivation unit 1 (TAU-1) between residues 101 and 370 required for fullligand-activated transcriptional activity[60]
    • Transactivationunit 5 (TAU-5) between residues 360–485 is responsible for theconstitutive activity(activity without bound ligand)[60]

Despite being highly disordered, the NTD domain adopts a 3D conformation in which two dynamically compact regions form, an N-terminal region (NR) and a C-terminal region (CR), each having distinct topological dynamics and function.[46]

Splice variants

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AR-V7is an androgen receptorsplice variantthat can be detected incirculating tumor cellsof metastaticprostate cancerpatients[64][65]and is predictive of resistance to some drugs (caused by missing Ligand-binding domain in this splice variant).[66]

Clinical significance

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High expression in androgen receptor has been linked to aggression and sex drive by affecting the HPA and HPG axis[67]

Aberrant androgen receptorcoregulatoractivity may contribute to the progression ofprostate cancer.[68][45]

Ligands

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Affinities[a][69]
Compound RBATooltip Relative binding affinity[b]
Metribolone 100
Dihydrotestosterone 85
Cyproterone acetate 7.8
Bicalutamide 1.4
Nilutamide 0.9
Hydroxyflutamide 0.57
Flutamide <0.0057
Notes:
  1. ^At androgen receptors; measured in human prostate tissue.
  2. ^Relative toMetribolone,which is by definition 100%

Agonists

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Mixed

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Antagonists

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As a drug target

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The AR is an important therapeutic target inprostate cancer.Thus many differentantiandrogenshave been developed, primarily targeting theligand-binding domainof the protein.[71]ARligandscan either be classified based on their structure (steroidalornonsteroidal) or based on their ability to activate or inhibit transcription (agonistsorantagonists).[72]Inhibitors that target alternative functional domains (N-terminal domain,DNA-binding domain) of the protein are still under development.[70]

Drug resistance

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Alteration of ARs may lead to treatment resistance (castration resistance) in prostate cancer as there may bemissense mutationsof theligand binding domain,amplifications of the gene coding for this receptor or in its enhancer, mostly, suggesting the presence of different subclones with different genotypes of these receptors.[45]

Interactions

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Androgen receptor has been shown tointeractwith:

See also

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References

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