AR (Androgen Receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease))

2008-01-01   Jason DAntonio 

The Johns Hopkins School of Medicine, Laboratory of John T. Isaacs, PhD, Cancer Research, Bldg 1, 1650 Orleans St., Rm 1M40, Baltimore, MD 21231, USA


Atlas Image
Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics



180 kb gene consisting of 8 exons


4,314 bp mRNA, 2,762 bp open reading frame


Atlas Image
Layout of the AR gene, mRNA and protein with indicated regulatory regions. Borrowed from Litvinov, et al. 2003, with permission.


919 amino acids (NCBI: P10275), MW = 99,187.57 daltons; -1.5 charge with an isoelectric pt = 6.3797; 10.6 kb AR transcript (NCBI: NM_000044 - partial sequence): 1.1kb 5 Untranslated Region (UTR) followed by the 2.7 kb Open Reading Frame (ORF) followed by the 6.8kb 3 UTR.
AR: AR isoform 1 [Homo sapiens] NP_000035 920 aa
AR45: AR isoform 2 [Homo sapiens] NP_001011645 388 aa
The AR coding sequence contains variable poly-aminoacid repeats in the amino-terminal domain:
1. poly-glutamine (CAG: Glu-Q): avg 22 repeats with normal polymorphic range from 8 to 35, shorter (<18) associated with increased AR transactivation and prostate cancer risk. CAG repeats in spinal and bulbar muscular atrophy patients range from 38 to 62.
2. poly-proline (Pro-P): avg 8.
3. poly-glycine (GGC: Gly-G): avg 23, with normal range from 10 to 31.


Embryonic tissue, prostate, testis, liver, eye, kidney, adrenal glands, thyroid, heart, breast/mammary gland, uterus, skeletal muscle, specific regions of the brain (CNS) including spinal and bulbar motor neurons.


Cytoplasm and nucleus


AR is a member of the steroid hormone receptor family of ligand-dependent nuclear receptors. AR functions include gene expression via actions as a DNA-binding transcription factor, cell cycle/proliferation regulation, cell-to-cell signaling, and intracellular signal transduction, leading to the regulation of biological processes such as development, cellular proliferation, differentiation and apoptosis. Some of the main target genes transcriptionally regulated by AR include AR, prostate specific antigen (PSA/hKlk3), hKlk2, hKlk4, prostate specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), cell cycle regulator p27, vascular endothelial growth factor (VEGF), TMPRSS2, and Nkx3.1.
Prostate organogenesis: The presence of AR is required in the mesodermal-derived embryonic urogenital sinus mesenchyme to trigger branching morphogenesis of endodermal-derived epithelial cells in the presence of androgens; subsequent AR expression in the developing epithelium drives secretory protein production. AR also plays an important role in the development of primary and secondary sexual characteristics, spermatogenesis, hormonal regulation of sexual drive, muscle growth, and male patterning of the brain.
Recent identification of the gene fusion between the 5 end of the AR-regulated serine protease TMPRSS2 (21q22.2) and the 3 end of ETS family of transcription factors ETV1 (7p21.3) and ERG (21q22.3) in a large frequency of prostate cancer cases raises new questions regarding AR function in prostate cancer. The gene rearrangement is thought to result in AR-induced expression of the suspected ETV1 or ERG oncogenes.


zebrafish (Danio rerio), dog (Canis familiaris), African clawed frog (Xenopus laevis), chimpanzee (Pan troglodytes), mouse (Mus musculus), chicken (Gallus gallus), rat (Rattus norvegicus), rainbow trout (Oncorhynchus mykiss).
No similarity-to-human data found for AR for:
pig (Sus scrofa), cow (Bos taurus), fruit fly (Drosophila melanogaster), worm (Caenorhabditis elegans), bakers yeast (Saccharomyces cerevisiae), tropical clawed frog (Silurana tropicalis), African malaria mosquito (Anopheles gambiae), thale cress (Arabidopsis thaliana), green algae (Chlamydomonas reinhardtii), soybean (Glycine max), barley (Hordeum vulgare), tomato (Lycopersicon esculentum), rice blast fungus (Magnaporthe grisea), rice (Oryza sativa), sugarcane (Saccharum officinarum), loblolly pine (Pinus taeda), corn (Zea mays), wheat (Triticum aestivum), Alicante grape (Vitis vinifera), bread mold (Neurospora crassa), fission yeast (Schizosaccharomyces pombe), sea squirt (Ciona intestinalis), amoeba (Dictyostelium discoideum), A. gosspyii yeast (Ashbya gossypii), K. lactis yeast (Kluyveromyces lactis), medicago trunc (Medicago truncatula), malaria parasite (Plasmodium falciparum), schistosome parasite (Schistosoma mansoni), sorghum (Sorghum bicolor), toxoplasmosis (Toxoplasma gondii).



Germ-line loss of function mutations in AR result in non-lethal loss of AR expression, a hallmark of androgen insensitivity syndrome. Individuals with AIS have a Y chromosome and functional testes, which produce high levels of testosterone; however, they lack male sex accessory organs, such as seminal vesicles and prostate, and are thus phenotypically female in both behavior and appearance.


Various somatic AR mutations have been identified, some of which are associated with prostate cancer, including the T877A mutation in the prostate cancer LNCaP cell line, which permits AR activation by progestins, estrogen, adrenal androgens, and anti-androgen hydroxyflutamide; however, the overall frequency of AR mutations in early, primary prostate cancer is <10%.
Polymorphic CAG repeats in exon 1 encoding a polyglutamine tract of variable length give rise to AR peptides of varying lengths: Shorter length (fewer CAG repeats) is associated with increased prostate cancer risk; increased length (greater CAG repeats) is associated with spinal and bulbar muscular atrophy and androgen insensitivity syndrome. For a more complete list of identified mutations, please visit

Implicated in

Androgenic alopecia, spinal and bulbar muscular dystrophy, androgen insensitivity syndrome due to AR mutations, benign prostatic hyperplasia, prostate adenocarcinoma
Entity name
Prostate adenocarcinoma (PCa)
PCa is the most commonly diagnosed cancer in American men and the second leading cause of cancer-related deaths. PCa predominantly occurs in the peripheral zone of the human prostate, with roughly 5 to 10% of cases found in the central zone. Disease development involves the temporal and spatial loss of the basal epithelial compartment accompanied by increased proliferation and de-differentiation of the luminal (secretory) epithelial cells. PCa is a slow developing disease that is typically found in men greater than 40 years of age, with an increasing rate of occurrence with increasing age.
Serum PSA testing combined with digital-rectal exams (DRE) are used to screen for the presence of disease. Given a positive DRE exam, additional tests including needle core biopsies are taken to histologically assess disease stage and grade. Localized, prostate-restricted disease is theoretically curable with complete removal of the prostate (radical prostatectomy). Patients with extra-prostatic disease are treated with chemotherapy, hormone (androgen ablation) therapy, radiation, and/or antiandrogens; however, no curative treatments are available for non-organ confined, metastatic disease.
Various forms of aneuploidy.
Fusion protein
Alterations in AR function are associated with the development of PCa due to a transition from paracrine AR signaling, traditionally involving the supporting mesenchyme instructing the terminal differentiation of the luminal epithelial cells, to autocrine AR signaling in luminal epithelial cells that promotes cell proliferation. Roughly 10% of PCa patients harbor AR mutations, suggesting that the prevalence of AR mutations, clinically, is low. Mutations that increase the signaling promiscuity of AR, AR gene amplification, as well as alterations in proteins that regulate AR levels/function contribute to de-regulated AR signaling.
Entity name
Benign Prostatic Hyperplasia (BPH)
Benign growth of the prostate, primarily occurring in the transitional zone of the prostate, results in urinary obstruction and lower urinary tract symptoms. AR function is associated with increased rates of epithelial cell proliferation, leading to increased size of the prostate gland. Originally thought of as benign prostatic hypertrophy, BPH has since been correctly characterized as a hyperplastic condition.
Patients with BPH are primarily treated with 2 types of agents to help reduce the size of the prostate, including Alpha-blockers: Flomax (tamsulosin), Uroxatral (alfuzosin), Hytrin (terazosin), Cardura (doxazosin); and 5-Alpha Reductase Inhibitors: Avodart (dutasteride), Proscar (finasteride). For symptoms unabated by medications, minimally invasive procedures: Transurethral microwave therapy (TUMT) and Transurethral needle ablation (TUNA) exist. More invasive surgeries: Transurethral resection of the prostate (TURP), Open prostatectomy (open surgery), Laser surgery, Transurethral incision of the prostate (TUIP) are available.
Occurring in the transitional zone of the prostate, it is currently believed that BPH does not lead to or initiate the development of PCa.
Entity name
Spinal and bulbar muscular atrophy
X-linked recessive form of spinal muscular atrophy
Spinal and bulbar muscular atrophy (SBMA, SMAX1), which is also known as Kennedy disease (KD), is caused by a trinucleotide CAG repeat expansion in exon 1 of the AR gene, resulting in decreased AR mRNA and protein levels. SBMA patients carry 38 to 62 CAG repeats; healthy individuals have 10 to 36.
SBMA is a neurodegenerative disease resulting in slow, progressive limb and bulbar muscle weakness, characterized by muscle atrophy due to neuron dysfunction. Also can cause gynecomastia. Current therapies include androgen deprivation therapy to curb the effects of pathologic AR signaling.
Entity name
Androgen insensitivity syndrome (AIS)
X-linked recessive disorder
Androgen insensitivity syndrome (AIS), Testicular feminization syndrome (TFM). Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal male (2A + XY) karyotype. Caused by mutations in the gene for the androgen receptor.


Pubmed IDLast YearTitleAuthors
110180102000Molecular genetics of prostate cancer.Abate-Shen C et al
156639862004Hormonal, cellular, and molecular regulation of normal and neoplastic prostatic development.Cunha GR et al
98900641998Physiology and pathophysiology of androgen action.Hiort O et al
124298192002Pattern of somatic androgen receptor gene mutations in patients with hormone-refractory prostate cancer.Hyytinen ER et al
174475232007[Paradigm shift in clinical trials for neurodegenerative diseases].Katsuno M et al
128431292003Is the Achilles' heel for prostate cancer therapy a gain of function in androgen receptor signaling?Litvinov IV et al
119317672002Formation of the androgen receptor transcription complex.Shang Y et al

Other Information

Locus ID:

NCBI: 367
MIM: 313700
HGNC: 644
Ensembl: ENSG00000169083


dbSNP: 367
ClinVar: 367
TCGA: ENSG00000169083


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Prostate cancerKEGGko05215
Pathways in cancerKEGGhsa05200
Prostate cancerKEGGhsa05215
Oocyte meiosisKEGGko04114
Oocyte meiosisKEGGhsa04114
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Signal TransductionREACTOMER-HSA-162582
Signaling by Rho GTPasesREACTOMER-HSA-194315
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases activate PKNsREACTOMER-HSA-5625740
Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3REACTOMER-HSA-5625886
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Nuclear Receptor transcription pathwayREACTOMER-HSA-383280
Ub-specific processing proteasesREACTOMER-HSA-5689880

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
251846302014AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.579
160797952005LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription.570
215758592011Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.424
196321762009Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer.396
215724382011Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA.396
190609102009Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.337
204785272010An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression.337
185939502008Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance.322
231178852013Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines.260
179401842007Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex.215


Jason DAntonio

AR (Androgen Receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease))

Atlas Genet Cytogenet Oncol Haematol. 2008-01-01

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