Androgen_recep | |||||||||
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Identifiers | |||||||||
Symbol | Androgen_recep | ||||||||
Pfam | PF02166 | ||||||||
InterPro | IPR001103 | ||||||||
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The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor [9] that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, [10] in the cytoplasm and then translocating into the nucleus. The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor. [11] [12]
The main function of the androgen receptor is as a DNA-binding transcription factor that regulates 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 sexual phenotype.
In some cell types, testosterone interacts directly with androgen receptors, whereas, in others, testosterone is converted by 5-alpha-reductase to dihydrotestosterone, an even more potent agonist for androgen receptor activation. [15] Testosterone appears to be the primary androgen receptor-activating hormone in the Wolffian duct, whereas dihydrotestosterone is the main androgenic hormone in the urogenital sinus, urogenital tubercle, and hair follicles. [16] Testosterone is therefore responsible primarily for the development of male primary sexual characteristics, whilst dihydrotestosterone is responsible for secondary male characteristics.
Androgens cause slow maturation of the bones, but more of the potent maturation effect comes from the estrogen produced by aromatization of androgens. Steroid users 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 in androgen insensitivity syndrome or estrogen insensitivity syndrome. [17]
Knockout-mice studies have shown that the androgen receptor is essential for normal female fertility, being required for development and full functionality of the ovarian follicles and ovulation, working through both intra-ovarian and neuroendocrine mechanisms. [18]
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 both osteoblasts and osteocytes. [19]
The AR plays a role in regulating female sexual, somatic, and behavioral functions. Experimental data using AR knockout female mice, provides evidence that the promotion of cardiac growth, kidney hypertrophy, cortical bone growth and regulation of trabecular bone 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) and partial (PAIS) which are a result of mutations in 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 ]
The primary mechanism of action for androgen receptors is direct regulation of gene 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 a conformational change in the receptor that, in turn, causes dissociation of heat shock proteins, transport from the cytosol into the cell nucleus, and dimerization. The androgen receptor dimer binds to a specific sequence of DNA known as a hormone 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 specific gene transcription. [25] Up-regulation or activation of transcription results in increased synthesis of messenger RNA, which, in turn, is translated by ribosomes to produce specific proteins. One of the known target genes of androgen receptor activation is the insulin-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 other DNA-binding proteins. One example is serum response factor, a protein that activates several genes that cause muscle growth. [27]
Androgen receptor is modified by post-translational modification through acetylation, [28] which directly promotes AR-mediated transactivation, apoptosis [29] and contact-independent growth of prostate cancer cells. [30] AR acetylation is induced by androgens [31] and determines recruitment into chromatin. [32] The AR acetylation site is a key target of NAD-dependent and TSA-dependent histone deacetylases [33] and long non-coding RNA. [34]
More recently, androgen receptors have been shown to have a second mode of action. As has been also found for other steroid hormone receptors such as estrogen receptors, androgen receptors can have actions that are independent of their interactions with DNA. [14] [35] Androgen receptors interact with certain signal transduction proteins 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 in ion 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.
In humans, the androgen receptor is encoded by the AR gene located on the X chromosome at Xq11–12. [36] [37]
At least 165 disease-causing mutations in this gene have been discovered. [38] The androgen insensitivity syndrome, formerly known as testicular feminization, is caused by a mutation in the androgen receptor gene on the X chromosome (locus: Xq11–Xq12). [39] The androgen receptor seems to affect neuron physiology and is defective in Kennedy's disease. [40] [41] In addition, point mutations and trinucleotide repeat polymorphisms have been linked to a number of additional disorders. [42]
The AR gene contains CAG repeats that 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.
The enhancer and 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]
Two isoforms of the androgen receptor (A and B) have been identified: [46]
Like other nuclear receptors, the androgen receptor is modular in structure and is composed of the following functional domains labeled A through F: [48]
AR-V7 is an androgen receptor splice variant that can be detected in circulating tumor cells of metastatic prostate cancer patients [63] [64] and is predictive of resistance to some drugs. [65]
High expression in androgen receptor has been linked to aggression and sex drive by affecting the HPA and HPG axis [66]
Aberrant androgen receptor coregulator activity may contribute to the progression of prostate cancer. [67] [45]
Compound | RBA [lower-alpha 2] |
---|---|
Metribolone | 100 |
Dihydrotestosterone | 85 |
Cyproterone acetate | 7.8 |
Bicalutamide | 1.4 |
Nilutamide | 0.9 |
Hydroxyflutamide | 0.57 |
Flutamide | <0.0057 |
Notes:
|
The AR is an important therapeutic target in prostate cancer. Thus many different antiandrogens have been developed, primarily targeting the ligand-binding domain of the protein. [70] AR ligands can either be classified based on their structure (steroidal or nonsteroidal) or based on their ability to activate or inhibit transcription (agonists or antagonists). [71] Inhibitors that target alternative functional domains (N-terminal domain, DNA-binding domain) of the protein are still under development. [69]
Alteration of ARs may lead to treatment resistance (castration resistance) in prostate cancer as there may be missense mutations of the ligand 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]
Androgen receptor has been shown to interact with:
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind.
Proline-, glutamic acid- and leucine-rich protein 1 (PELP1) also known as modulator of non-genomic activity of estrogen receptor (MNAR) and transcription factor HMX3 is a protein that in humans is encoded by the PELP1 gene. is a transcriptional corepressor for nuclear receptors such as glucocorticoid receptors and a coactivator for estrogen receptors.
Estrogen receptor alpha (ERα), also known as NR3A1, is one of two main types of estrogen receptor, a nuclear receptor that is activated by the sex hormone estrogen. In humans, ERα is encoded by the gene ESR1.
Transcription factor Jun is a protein that in humans is encoded by the JUN gene. c-Jun, in combination with protein c-Fos, forms the AP-1 early response transcription factor. It was first identified as the Fos-binding protein p39 and only later rediscovered as the product of the JUN gene. c-jun was the first oncogenic transcription factor discovered. The proto-oncogene c-Jun is the cellular homolog of the viral oncoprotein v-jun. The viral homolog v-jun was discovered in avian sarcoma virus 17 and was named for ju-nana, the Japanese word for 17. The human JUN encodes a protein that is highly similar to the viral protein, which interacts directly with specific target DNA sequences to regulate gene expression. This gene is intronless and is mapped to 1p32-p31, a chromosomal region involved in both translocations and deletions in human malignancies.
The nuclear receptor coactivator 1 (NCOA1), also called steroid receptor coactivator-1 (SRC-1), is a transcriptional coregulatory protein that contains several nuclear receptor–interacting domains and possesses intrinsic histone acetyltransferase activity. It is encoded by the gene NCOA1.
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).
The small heterodimer partner (SHP) also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.
Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the RELA gene.
RAR-related orphan receptor alpha (RORα), also known as NR1F1 is a nuclear receptor that in humans is encoded by the RORA gene. RORα participates in the transcriptional regulation of some genes involved in circadian rhythm. In mice, RORα is essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient. In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.
Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the RHOA gene. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. It acts upon several effectors. Among them, ROCK1 and DIAPH1 are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billion years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.
Retinoic acid receptor alpha (RAR-α), also known as NR1B1, is a nuclear receptor that in humans is encoded by the RARA gene.
Transforming growth factor beta-1-induced transcript 1 protein is a protein that in humans is encoded by the TGFB1I1 gene. Often put together with and studied alongside TGFB1I1 is the mouse homologue HIC-5. As the name suggests, TGFB1I1 is an induced form of the larger family of TGFB1. Studies suggest TGFB1I1 plays a role in processes of cell growth, proliferation, migration, differentiation and senescence. TGFB1I1 is most localized at focal adhesion complexes of cells, although it may be found active in the cytosol, nucleus and cell membrane as well.
Four and a half LIM domains protein 2 also known as FHL-2 is a protein that in humans is encoded by the FHL2 gene. LIM proteins contain a highly conserved double zinc finger motif called the LIM domain.
Non-POU domain-containing octamer-binding protein (NonO) is a protein that in humans is encoded by the NONO gene.
Nuclear receptor coactivator 4, also known as Androgen Receptor Activator (ARA70), is a protein that in humans is encoded by the NCOA4 gene. It plays an important role in ferritinophagy, acting as a cargo receptor, binding to the ferritin heavy chain and latching on to ATG8 on the surface of the autophagosome.
The testicular receptor 2 (TR2) also known as NR2C1 is protein that in humans is encoded by the NR2C1 gene. TR2 is a member of the nuclear receptor family of transcription factors.
Steroid receptor RNA activator 1 also known as steroid receptor RNA activator protein (SRAP) is a protein that in humans is encoded by the SRA1 gene. The mRNA transcribed from the SRA1 gene is a component of the ribonucleoprotein complex containing NCOA1. This functional RNA also encodes a protein.
E3 ubiquitin-protein ligase RNF14 is an enzyme that in humans is encoded by the RNF14 gene.
Melanoma-associated antigen 11 is a protein that in humans is encoded by the MAGEA11 gene. It is also involved in the androgen and progesterone receptor signaling pathways.
EPI-001 is the first inhibitor of the androgen receptor amino-terminal domain. The single stereoisomer of EPI-001, EPI-002, is a first-in-class drug that the USAN council assigned a new stem class "-aniten" and the generic name "ralaniten". This distinguishes the anitens novel molecular mechanism from anti androgens that bind the C-terminus ligand-binding domain and have the stem class "lutamide". EPI-001 and its stereoisomers and analogues were discovered by Marianne Sadar and Raymond Andersen, who co-founded the pharmaceutical company ESSA Pharma Inc for the clinical development of anitens for the treatment of castration-resistant prostate cancer (CRPC).