AR

GeneName

AR

Summary

The androgen receptor (AR), also known as BAR, is a 99 kDa nuclear receptor that plays a pivotal role in mediating the effects of androgens, such as testosterone and dihydrotestosterone, in various tissues including the prostate, testes, and skeletal muscle. It is primarily expressed in the nucleus and cytoplasm, where it binds to androgen response elements in target gene promoters, regulating transcriptional activity. AR is involved in numerous biological processes including male gonad development, epithelial cell differentiation in the prostate gland, and cellular responses to steroid hormones. Its functions extend to chromatin binding and interaction with various co-regulators, making it essential for proper cellular signalling and development.

Importance

The androgen receptor is relevant to: - Prostate cancer research due to its role in tumour growth and progression, as AR signalling can promote cancer cell proliferation. - Hormonal therapies targeting AR in conditions like androgen insensitivity syndrome and hypogonadism. - Understanding male reproductive health and disorders, including spermatogenesis and Leydig cell differentiation. - Investigating the impact of androgens on muscle development and maintenance, with implications for age-related muscle loss and anabolic therapies.

Top Products

For researchers investigating the androgen receptor (AR), we highly recommend the top-selling recombinant antibody, Anti-Androgen Receptor antibody [EPR1535(2)] (ab133273). This well-cited antibody has garnered 163 citations, reflecting its reliability and trust within the scientific community. It has been validated for use in several applications, including Western blotting (WB), immunohistochemistry (IHC), and immunocytochemistry (ICC), making it a versatile choice for various experimental needs. The recombinant nature of this antibody ensures batch-to-batch consistency, providing researchers with confidence in their results.

Abcam Product Citation Summary

The data indicates a significant focus on the androgen receptor (AR) in various contexts, particularly in human and mouse models. Studies often utilise Western blotting and immunohistochemistry to explore the effects of treatments such as selinexor and KPT-8602, as well as the implications of castration and neurodegeneration in SOD1G93A mice. The diversity of species and applications highlights the relevance of AR in both cancer research and neurobiology.

Abcam Product Citation Table

Domain

Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. In the presence of bound steroid the ligand-binding domain interacts with the N-terminal modulating domain, and thereby activates AR transcription factor activity. Agonist binding is required for dimerization and binding to target DNA. The transcription factor activity of the complex formed by ligand-activated AR and DNA is modulated by interactions with coactivator and corepressor proteins (PubMed:25091737). Interaction with RANBP9 is mediated by both the N-terminal domain and the DNA-binding domain. Interaction with EFCAB6/DJBP is mediated by the DNA-binding domain.

Function

The protein expressed by the AR gene functions as a steroid hormone receptor, a type of ligand-activated transcription factor that regulates eukaryotic gene expression and influences cellular proliferation and differentiation in target tissues. Its transcription factor activity can be modulated by coactivator and corepressor proteins, such as ZBTB7A, which recruits NCOR1 and NCOR2 to androgen response elements on target genes, thereby negatively regulating androgen receptor signaling and androgen-induced cell proliferation. The transcription activation can also be down-regulated by NR0B2. The protein is activated, though not phosphorylated, by HIPK3 and ZIPK/DAPK3. Notably, isoforms 3 and 4 of this protein lack the C-terminal ligand-binding domain and may thus constitutively activate transcription of specific gene sets independently of steroid hormones. This supplementary information is collated from multiple sources and compiled automatically.

Involvement in disease

Androgen insensitivity syndrome

AIS

An X-linked recessive form of pseudohermaphroditism due end-organ resistance to androgen. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal 46,XY karyotype.

None

The disease is caused by variants affecting the gene represented in this entry.

Spinal and bulbar muscular atrophy X-linked 1

SMAX1

An X-linked recessive form of spinal muscular atrophy. Spinal muscular atrophy refers to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAX1 occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. It is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia. The disorder is clinically similar to classic forms of autosomal spinal muscular atrophy.

None

The disease is caused by variants affecting the gene represented in this entry. Caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.

Prostate cancer, hereditary, X-linked 3

HPCX3

A condition associated with familial predisposition to cancer of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor.

Androgen insensitivity, partial

PAIS

A disorder that is characterized by hypospadias, hypogonadism, gynecomastia, genital ambiguity, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance. Some patients present azoospermia or severe oligospermia without other clinical manifestations.

None

The disease is caused by variants affecting the gene represented in this entry.

Hypospadias 1, X-linked

HYSP1

A common malformation in which the urethra opens on the ventral side of the penis, due to developmental arrest of urethral fusion. The opening can be located glandular, penile, or even more posterior in the scrotum or perineum. Hypospadias is a feature of several syndromic disorders, including the androgen insensitivity syndrome and Opitz syndrome.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Sumoylated on Lys-388 (major) and Lys-521. Ubiquitinated. Deubiquitinated by USP26. 'Lys-6' and 'Lys-27'-linked polyubiquitination by RNF6 modulates AR transcriptional activity and specificity.

Phosphorylated in prostate cancer cells in response to several growth factors including EGF. Phosphorylation is induced by c-Src kinase (CSK). Tyr-535 is one of the major phosphorylation sites and an increase in phosphorylation and Src kinase activity is associated with prostate cancer progression. Phosphorylation by TNK2 enhances the DNA-binding and transcriptional activity and may be responsible for androgen-independent progression of prostate cancer. Phosphorylation at Ser-83 by CDK9 regulates AR promoter selectivity and cell growth. Phosphorylation by PAK6 leads to AR-mediated transcription inhibition.

Palmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid intracellular signaling via ERK and AKT kinases and cAMP generation.

Sequence Similarities

Belongs to the nuclear hormone receptor family. NR3 subfamily.

Tissue Specificity

Isoform 2

Mainly expressed in heart and skeletal muscle.

Isoform 3

Expressed in basal and stromal cells of the prostate (at protein level).

Cellular localization

• Nucleus
• Cytoplasm
• Detected at the promoter of target genes (PubMed:25091737). Predominantly cytoplasmic in unligated form but translocates to the nucleus upon ligand-binding. Can also translocate to the nucleus in unligated form in the presence of RACK1.

Alternative names

DHTR, NR3C4, AR, Androgen receptor, Dihydrotestosterone receptor, Nuclear receptor subfamily 3 group C member 4

Database links

swissprot:P10275 omim:313700 swissprot:E7EVX6 swissprot:C0JKD3 entrezGene:367

Other research areas

• Oncology