androgen receptor; dihydrotestosterone receptor; nuclear receptor subfamily 3 group C member 4 (AR, DHTR, NR3C4)
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Function
- nuclear hormone receptor
- agonist binding is required for dimerization & binding to target DNA
- transcription factor activity of the complex formed by ligand-activated AR & DNA is modulated by interactions with coactivator & corepressor proteins
- cytoplasmic anchoring &/or assembly associated with heat shock proteins hsp70 & hsp90 & immunophilin p59FKBP
- in the absence of ligand, steroid hormone receptors may be weakly associated with nuclear components
- hormone binding greatly increases receptor affinity
- the hormone-receptor complex appears to recognize discrete DNA sequences upstream of transcriptional start sites
- transcriptional activity is enhanced by binding to RANBP9
- transcription activation is down-regulated by NR0B2
- activated, but not phosphorylated, by HIPK3
- binds DNA as a homodimer
- part of a ternary complex containing AR, EFCAB6/DJBP & PARK7
- interacts with HIPK3 & NR0B2 in the presence of androgen
- the ligand binding domain interacts with MYST2/HBO1 in the presence of dihydrotestosterone
- interacts with EFCAB6/DJBP, PELP1, PQBP1, RANBP9, RBAK, SPDEF, SRA1, TGFB1I1, ZNF318 & RREB1
- interacts with ZMIZ1/ZIMP10 & ZMIZ2/ZMIP7 which both enhance its transactivation activity
- interacts with SLC30A9 & RAD54L2/ARIP4 (putative)
- interacts via the ligand-binding domain with LXXLL & FXXLF motifs from NCOA1, NCOA2, NCOA3, NCOA4 & MAGEA11
- The AR N-terminal poly-Gln region binds Ran resulting in enhancement of AR-mediated transactivation; Ran-binding decreases as the poly-Gln length increases
- sumoylated on Lys-386 (major) & Lys-520
- phosphorylated in prostate cancer cells in response to several growth factors including EGF
- phosphorylation is induced by c-Src kinase (CSK)
- Tyr-534 is one of the major phosphorylation sites & an increase in phosphorylation & Src kinase activity is associated with prostate cancer progression
Structure
- composed of three domains:
- modulating N-terminal domain
- DNA-binding domain
- C-terminal steroid-binding domain
- in the presence of bound steroid, ligand-binding domain interacts with the N-terminal modulating domain, & thus activates AR transcription factor activity
- interaction with RANBP9 is mediated by both the N-terminal domain & the DNA-binding domain
- interaction with EFCAB6/DJBP is mediated by the DNA-binding domain
- belongs to the nuclear hormone receptor family, NR3 subfamily
- contains 1 nuclear receptor DNA-binding domain
Compartment
Pathology
- genetic variation in AR can be responsible of androgenetic alopecia
- defects in AR may play a role in prostate cancer
- metastatic prostate cancer
- level of tyrosine phosphorylation may serve as a diagnostic tool to predict patient outcome with hormone-ablation therapy
- inhibition of tyrosine phosphorylation may be an effective intervention target for hormone-refractory prostate cancer
- defects in AR are the cause of
Polymorphism
- the poly-Gln region of AR is highly polymorphic; the number of Gln varies in the population (17-26); a smaller size of the poly-Gln region may be associated with the development of prostate cancer
- the poly-Gly region of AR is polymorphic & ranges from 24-31 gly; a poly-Gly region =< 23 may be associated with development of androgenetic alopecia
Laboratory
More general terms
Additional terms
- androgen or anabolic steroid
- prostate cancer
- X-linked bulbospinal muscular atrophy (Kennedy's disease)
References
- ↑ Simental JA, Sar M, Lane MV, French FS, Wilson EM. Transcriptional activation and nuclear targeting signals of the human androgen receptor. J Biol Chem. 1991 Jan 5;266(1):510-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/1985913
- ↑ Ross CA, McInnis MG, Margolis RL, Li SH. Genes with triplet repeats: candidate mediators of neuropsychiatric disorders. Trends Neurosci. 1993 Jul;16(7):254-60. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7689767
- ↑ Androgen receptor gene mutations database http://www.mcgill.ca/androgendb/
- ↑ GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=AR
- ↑ Wikipedia; Note: androgen receptor entry http://en.wikipedia.org/wiki/androgen_receptor
- ↑ UniProt http://www.uniprot.org/uniprot/P10275.html
Database
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:367
- OMIM: https://mirror.omim.org/entry/109200
- OMIM: https://mirror.omim.org/entry/300068
- OMIM: https://mirror.omim.org/entry/308370
- OMIM: https://mirror.omim.org/entry/312300
- OMIM: https://mirror.omim.org/entry/313200
- OMIM: https://mirror.omim.org/entry/313700
- UniProt: http://www.uniprot.org/uniprot/P10275.html