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Understanding Androgen Receptor (AR)
By: Road2HardCoreIron Date: March 28, 2023, 2:11 pm
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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.
Function
Effect on development
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]
Maintenance of male skeletal integrity
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]
Role in females
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]
Mechanism of action
Genomic
The primary mechanism of action for androgen receptors is direct
regulation of gene transcription. 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. Androgen
receptors interact with other proteins in the nucleus, resulting
in up- or down-regulation of specific gene transcription.[20]
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).[21] 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.[22]
Androgen receptor is modified by post-translational modification
through acetylation,[23] which directly promotes AR-mediated
transactivation, apoptosis[24] and contact-independent growth of
prostate cancer cells.[25] AR acetylation is induced by
androgens[26] and determines recruitment into chromatin.[27] The
AR acetylation site is a key target of NAD-dependent and
TSA-dependent histone deacetylases[28] and long non-coding
RNA.[29]
Non-genomic
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][30] 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.
Genetics
Gene
In humans, the androgen receptor is encoded by the AR gene
located on the X chromosome at Xq11–12.[31][32]
Deficiencies
At least 165 disease-causing mutations in this gene have been
discovered. [33] 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).[34] The androgen receptor seems to affect neuron
physiology and is defective in Kennedy's disease.[35][36] In
addition, point mutations and trinucleotide repeat polymorphisms
have been linked to a number of additional disorders.[37]
CAG repeats
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,[38][39] with African-Americans having
fewer repeats than non-Hispanic white Americans.[38] The racial
trends in CAG repeats parallels the incidence and mortality of
prostate cancer in these groups.
Mutations
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.[40]
Structure
Structural domains of the two isoforms (AR-A and AR-B) of the
human androgen receptor. Numbers above the bars refer to the
amino acid residues that separate the domains starting from the
N-terminus (left) to C-terminus (right). NTD = N-terminal
domain, DBD = DNA-binding domain, LBD = ligand-binding domain,
AF = activation function.
Isoforms
Two isoforms of the androgen receptor (A and B) have been
identified:[41]
AR-A – 87 kDa; N-terminus truncated (lacks the first 187 amino
acids), which results from in vitro proteolysis.[42]
AR-B – 110 kDa; full length
Domains
Like other nuclear receptors, the androgen receptor is modular
in structure and is composed of the following functional domains
labeled A through F:[43]
A/B) – N-terminal regulatory domain contains:[44]
activation function 1 (AF-1) between residues 101 and 370
required for full ligand-activated transcriptional activity
activation function 5 (AF-5) between residues 360–485 is
responsible for the constitutive activity (activity without
bound ligand)
dimerization surface involving residues 1–36 (containing the
FXXLF motif; where F = phenylalanine, L = leucine, and X = any
amino acid residue) and 370–494, both of which interact with the
ligand binding domain (LBD) in an intramolecular[45][46][47]
head-to-tail interaction[48][49][50]
C) – DNA binding domain (DBD)
D) – Hinge region; flexible region that connects the DBD with
the LBD; along with the DBD, contains a ligand dependent nuclear
localization signal[51]
E) – Ligand binding domain (LBD) containing
activation function 2 (AF-2), responsible for agonist induced
activity (activity in the presence of bound agonist)
AF-2 binds either the N-terminal FXXFL motif intramolecularly or
coactivator proteins (containing the LXXLL or preferably FXXFL
motifs)[50]
A ligand dependent nuclear export signal[52]
F) – C-terminal domain
Splice variants
AR-V7 is an androgen receptor splice variant that can be
detected in circulating tumor cells of metastatic prostate
cancer patients[53][54] and is predictive of resistance to some
drugs.[55]
Clinical significance
High expression in androgen receptor has been linked to
aggression and sex drive by affecting the HPA and HPG axis[56]
Aberrant androgen receptor coregulator activity may contribute
to the progression of prostate cancer.[57][40]
Ligands
vte Affinities[a][58]
Compound
Metribolone
Dihydrotestosterone
Cyproterone acetate
Bicalutamide
Nilutamide
Hydroxyflutamide
Flutamide
Notes:
At androgen receptors; measured in human prostate tissue.
Relative to Metribolone, which is by definition 100%
Agonists
Endogenous androgens (e.g., testosterone, dihydrotestosterone,
androstenedione, androstenediol, dehydroepiandrosterone)
Synthetic androgens (e.g., methyltestosterone, metandienone,
nandrolone, trenbolone, oxandrolone, stanozolol)
Mixed
Selective androgen receptor modulators (e.g., andarine,
enobosarm)
Antagonists
Steroidal antiandrogens (e.g., cyproterone acetate,
chlormadinone acetate, spironolactone, oxendolone)
Nonsteroidal antiandrogens (e.g., flutamide, nilutamide,
bicalutamide, enzalutamide, apalutamide, RU-58841)
N-Terminal domain antiandrogens (e.g., bisphenol A, EPI-001,
ralaniten, JN compounds)[59]
As a drug target
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.[60] 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).[61]
Inhibitors that target alternative functional domains
(N-terminal domain, DNA-binding domain) of the protein are still
under development.[59]
Drug resistance
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.[40]
Interactions
Androgen receptor has been shown to interact with:
AKT1,[62]
BAG1,[63][64][65]
Beta-catenin,[66][67][68][69][70][71]
BRCA1,[72][73]
C-jun,[74]
Calmodulin 1,[75]
Caveolin 1,[76]
CDK9,[77]
COX5B,[78]
CREB-binding protein,[79][80][81][82]
Cyclin D1,[83][84][85][86]
Cyclin-dependent kinase 7,[87]
DACH1,[88]
Death associated protein 6,[89]
L-DOPA,[90]
EFCAB6,[91]
Epidermal growth factor receptor,[92][93]
FOXO1,[94]
GAPDH,[95]
Gelsolin,[96]
GNB2L1,[97]
GSK3B,[98]
HDAC1,[99]
HSP90AA1,[100][101]
HTATIP,[99]
MAGEA11,[102][103]
MED1,[104]
MYST2,[105]
NCOA1,[67][106][107]
NCOA2,[66][81][102][108][109]
NCOA3,[108][110][111]
NCOA4,[62][109][112][113][114][115][116][117][118]
NCOA6,[119]
NCOR2,[66][120][121]
NONO,[81]
p300,[122]
PA2G4,[123]
PAK6,[124][125]
PATZ1,[126]
PIAS2,[127][128]
PRPF6,[129]
PTEN,[130]
RAD9A,[131]
RANBP9,[132]
RCHY1,[133]
Retinoblastoma protein,[134][135]
RNF14,[109][112][136][137]
RNF4,[126][138][139]
SART3,[140]
SIRT1,[28]
SMAD3,[141][142][143]
Small heterodimer partner,[144]
Src,[130][145][146]
SRY,[147]
STAT3,[148][149]
SVIL,[150]
Testicular receptor 2,[151]
Testicular receptor 4,[152]
TGFB1I1,[112][153]
TMF1,[154]
TRIM68,[155]
UBE2I,[66][67][156][157][158][159]
UXT,[160] and
ZMIZ1.[161]
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