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AR

Official Full Name
androgen receptor
Organism
Homo sapiens
GeneID
367
Background
The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy's disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]
Synonyms
KD; AIS; AR8; TFM; DHTR; SBMA; HYSP1; NR3C4; SMAX1; HUMARA;
Bio Chemical Class
Nuclear hormone receptor
Protein Sequence
MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQQQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQSALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSADLKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELCKAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAGKSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQSRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAAGPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAPYGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRLETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKLTVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWAKALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSRMYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELDRIIACKRKNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVDFPEMMAEIISVQVPKILSGKVKPIYFHTQ
Open
Disease
Acne vulgaris, Acute myeloid leukaemia, Alcoholic liver disease, Alopecia, Bladder cancer, Breast cancer, Cachexia, Cardiovascular disease, Chronic kidney disease, Chronic obstructive pulmonary disease, Contraceptive management, Cystic fibrosis, Dissociative neurological symptom disorder, Female pelvic pain, Heart failure, Hypo-osmolality/hyponatraemia, Low bone mass disorder, Mammary tumour, Muscle disorder, Muscular dystrophy, Oesophagitis, Pain, Pituitary gland disorder, Prostate cancer, Prostate hyperplasia, Solid tumour/cancer, Testicular dysfunction, Thrombosis
Approved Drug
18 +
Clinical Trial Drug
30 +
Discontinued Drug
12 +

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Detailed Information

With three primary functional domains—the N-terminal domain (NTD), the DNA-binding domain (DBD), and the androgen-binding domain (ABD)—the androgen receptor gene (AR) spans about 90 kilobases (kb). Acting as a steroid hormone-activated transcription factor, the AR is absolutely important for gene control, cell growth, and differentiation. The receptor alters conformally as it binds to its hormone ligand. It dimerizes, separates from accessory proteins, moves into the nucleus, and then activates androgen-responsive gene transcription.

Polymorphic Features and Associated Diseases

Two polymorphic trinucleotide repeat sequences in the AR gene encode polyglutamine and polyglycine tracts within its N-terminal transactivation region. Kennedy's illness, often referred to as spinal bulbar muscle atrophy, results from a notable pathogenic range of 38-62 repeats from the usual range of 9-34 repetitions. Furthermore linked to either complete androgen insensitivity syndrome (CAIS) are mutations in the AR gene. Alternative splicing, which generates many transcript variants each encoding different isoforms of the receptor, emphasizes even more the intricacy of the gene.

Biological Significance and Pathways

Considered a Protein Coding gene, the AR gene is tightly linked to a number of disorders including spinal and bulbar muscular atrophy, partial androgen insensitivity, and androgen insensitivity. The linked biological processes include Rho GTPase signaling and transcription of genes. Activities related to this gene that fit gene ontology (GO) annotations include chromatin binding and DNA-binding transcription factor activity. Moreover, NR3C2 is a crucial paralog of the AR gene that helps to explain the intricacy of steroid hormone signaling.

Role as a Steroid Hormone Receptor

Comprising numerous additional receptors including mineralocorticoids, progesterones, and glucocorticoids, androgen receptors (ARs), also known as dihydrotestosterone receptors, belong to the nuclear hormone receptor superfamily. Mostly expressed in many organs, including the prostate, mammary glands, and bone marrow, the AR is found in This broad expression pattern emphasizes how important androgens—mostly testosterone and dihydrotestosterone (DHT)—are in mediating different biological effects all over the human body.

Figure 1 illustrates the two mechanisms of ligand-dependent androgen receptor (AR) action: DNA binding-dependent (DBD) and non-DNA binding (DBD) mechanisms.Figure 1. Mechanisms of androgen receptor (AR) activation. (Lonergan PE, et al., 2011)

Discovery and Historical Context

Beginning in the middle of the 20th century with the separation of several steroids and their metabolites from biological sources, the study of steroid hormones and their receptors has a rich legacy. Among the first hormones to be separate, testosterone spurred further research on its receptor. Later, mainwaring et al. extensively characterized the DHT receptor in rat ventral prostate using a significant work by Unhjem et al. identifying a high-affinity, low-capacity protein that bound to DHT. Jorge A. Simental et al. clarified in 1991 the method by which androgens go via AR into the nucleus, therefore sparking further study on the AR gene. Currently, PubMed has about 30,000 AR-related papers; yearly growth in the body of knowledge is clearly evident.

Structural Domains of the Androgen Receptor

Found on the X chromosome (Q11–12), the human AR gene has eight exons and codes for a protein with a molecular weight of around 110 kDa and 919 amino acids. The N-terminal domain (NTD), the DNA-binding domain (DBD), the ligand-binding domain (LBD), and a hinge region between the LBD and DBD define four different structural and functional domains for the protein.

Low conservation defines the NTD, but among steroid hormone nuclear receptors the DBD is the most extensively conserved. Two zinc fingers make up the DBD; they interact with certain DNA consensus sequences to let the AR attach to the enhancer and promoter areas of AR-regulated genes. Either promoting or inhibiting gene expression, this binding helps the NTD and LBD to engage in transcriptional activity.

Ligand Binding and Activation

AR stays inactive in the cytoplasm without ligands, bound to many heat shock proteins (HSPs) including HSP90, HSP70, and HSP56. Usually transformed to DHT by the enzyme 5α-reductase upon ligand binding, testosterone may also bind to AR. DHT does, however, show a far greater binding affinity—about two to ten times that of testosterone. The AR conformational change brought about by hormone binding causes heat shock proteins to dissociate and translocation of AR into the nucleus to follow.

AR creates homodimers—either in a head-to-head or head-to-tail orientation—once in the nucleus, which subsequently binds to androgen response elements (AREs) on target genes. This interaction causes chromatin remodeling, opening promoter areas, and engaging co-activators and transcription factors, therefore promoting the expression of genes linked to several physiological processes, including cell differentiation and tissue formation.

Role in Prostate Development and Disease

Normal prostate development and growth as well as in the course of prostate cancer depend on the AR. Studies show that androgens are essential for preserving prostate cell viability; without them, prostate cells die. On the other hand, normal androgen levels help prostate cells to grow and differentiate constantly. On the other hand, too high or too low AR responsiveness or too strong androgen release may cause uncontrolled development, which greatly increases the risk of prostate cancer.

Genetic Variability and Cancer Risk

Prostate cancer risk factors for AR are closely correlated with its activity and expression levels, which reflect its genetic variations. Receptor function has been demonstrated to be influenced by the variability in the first exon of the AR gene, especially in CAG and GGC repeat sequences, therefore influencing prostate epithelial cell proliferation and the risk of prostate cancer development.

Furthermore contributing to many additional disorders like early-onset baldness, cryptorchidism, and androgen insensitivity syndrome are mutations and changes in the AR gene. Research shows that almost all primary prostate tumors have AR expression; the expression levels match those of primary and metastatic lesions. Significantly linked with aberrant AR signaling, the progression of prostate cancer into castration-resistant prostate cancer (CRPC) is characterized by a complex interaction of signaling networks.

References:

  1. Davey RA, Grossmann M. Androgen Receptor Structure, Function, and Biology: From Bench to Bedside. Clin Biochem Rev. 2016;37(1):3-15.
  2. Azad AA, Volik SV, Wyatt AW, et al. Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer. Clin Cancer Res. 2015 May 15;21(10):2315-24.
  3. Pazo C, Webster RM. The prostate cancer drug market. Nat Rev Drug Discov. 2021 Sep;20(9):663-664.
  4. He Y, Xu W, Xiao YT, et al. Targeting signaling pathways in prostate cancer: mechanisms and clinical trials. Signal Transduct Target Ther. 2022 Jun 24;7(1):198.
  5. Lonergan PE, Tindall DJ. Androgen receptor signaling in prostate cancer development and progression. J Carcinog. 2011;10:20.
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