Human androgen receptor and androgen binding

The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

that is activated by binding any of the

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This inc ...

hormones A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and beh ...

, including

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...

and

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...

in the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

and then translocating into the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

. The androgen receptor is most closely related to the

progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resid ...

, and

progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural product, natural female sex hormone progesterone in the body. A progestin is a ''synthetic co ...

s in higher dosages can block the androgen receptor. The main function of the androgen receptor is as a DNA-binding

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

that regulates gene expression; however, the androgen receptor has other functions as well. Androgen-regulated genes are critical for the development and maintenance of the male sexual

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

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 An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

for androgen receptor activation. Testosterone appears to be the primary androgen receptor-activating hormone in the

Wolffian duct The mesonephric duct (also known as the Wolffian duct, archinephric duct, Leydig's duct or nephric duct) is a paired organ that forms during the embryonic development of humans and other mammals and gives rise to male reproductive organs. Stru ...

, whereas dihydrotestosterone is the main androgenic hormone in the

urogenital sinus The urogenital sinus is a part of the human body only present in the development of the urinary and reproductive organs. It is the ventral part of the cloaca, formed after the cloaca separates from the anal canal during the fourth to seventh we ...

, urogenital tubercle, and

hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between h ...

s. Testosterone is therefore responsible primarily for the development of male

primary sexual characteristics Sexual characteristics are physical traits of an organism (typically of a sexually dimorphic organism) which are indicative of its biological sex. These can include sex organs used for reproduction and secondary sex characteristics which disting ...

, 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 Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

produced by

aromatization Aromatization is a chemical reaction in which an aromatic system is formed from a single nonaromatic precursor. Typically aromatization is achieved by dehydrogenation of existing cyclic compounds, illustrated by the conversion of cyclohexane int ...

of androgens.

Steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

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 Androgen insensitivity syndrome (AIS) is a difference in sex development involving hormonal resistance due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY ( karyotypically male) births. The condition results in the partial o ...

estrogen insensitivity syndrome Estrogen insensitivity syndrome (EIS), or estrogen resistance, is a form of congenital estrogen deficiency or hypoestrogenism which is caused by a defective estrogen receptor (ER) – specifically, the estrogen receptor alpha (ERα) – that resu ...

Knockout-mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "Gene knockout, knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They ...

studies have shown that the androgen receptor is essential for normal female fertility, being required for development and full functionality of the

ovarian follicle An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with th ...

s and

ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized ...

, working through both intra-ovarian and

neuroendocrine Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules ( hormones) into the blood. In this way they b ...

mechanisms.

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 Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...

and

osteocytes An osteocyte, an oblate shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide and ...

Role in females

The AR plays a role in regulating female sexual, somatic, and behavioral functions. Experimental data using AR

knockout A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, a ...

female mice, provides evidence that the promotion of cardiac growth, kidney hypertrophy, cortical bone growth and regulation of

trabecular A trabecula (plural trabeculae, from Latin for "small beam") is a small, often microscopic, tissue element in the form of a small beam, strut or rod that supports or anchors a framework of parts within a body or organ. A trabecula generally has ...

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 Complete may refer to: Logic * Completeness (logic) * Completeness of a theory, the property of a theory that every formula in the theory's language or its negation is provable Mathematics * The completeness of the real numbers, which implies t ...

(CAIS) and

partial Partial may refer to: Mathematics * Partial derivative, derivative with respect to one of several variables of a function, with the other variables held constant ** ∂, a symbol that can denote a partial derivative, sometimes pronounced "partial ...

(PAIS) which are a result of

mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

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.

Mechanism of action

Genomic

The primary mechanism of action for androgen receptors is direct regulation of

gene transcription Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...

. The binding of an androgen to the androgen receptor results in a

conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...

in the receptor that, in turn, causes dissociation of

heat shock protein Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including expo ...

s, transport from the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

into the

cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...

, and

dimerization A dimer () (''wikt:di-, di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, Covalent bond, covalent or Intermolecular force, intermolecular. Dimers also have significant im ...

. The androgen receptor dimer binds to a specific sequence of DNA known as a

hormone response element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein binds ...

. Androgen receptors interact with other proteins in the nucleus, resulting in up- or down-regulation of specific

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

transcription. Up-regulation or activation of transcription results in increased synthesis of

messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...

, which, in turn, is translated by

ribosomes Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to f ...

to produce specific proteins. One of the known target genes of androgen receptor activation is the

insulin-like growth factor 1 receptor The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 ( IGF-1) and by a related hormone called IGF-2. ...

(IGF-1R). 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 DNA-binding proteins are proteins that have DNA-binding domains and thus have a specific or general affinity for single- or double-stranded DNA. Sequence-specific DNA-binding proteins generally interact with the major groove of B-DNA, becaus ...

. One example is

serum response factor Serum response factor, also known as SRF, is a transcription factor protein. Function Serum response factor is a member of the MADS (MCM1, Agamous, Deficiens, and SRF) box superfamily of transcription factors. This protein binds to the serum ...

, a protein that activates several genes that cause muscle growth. Androgen receptor is modified by

post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...

through

acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...

, which directly promotes AR-mediated

transactivation In the context of gene regulation: transactivation is the increased rate of gene expression triggered either by biological processes or by artificial means, through the expression of an intermediate transactivator protein. In the context of recep ...

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

and contact-independent growth of

prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...

cells. AR acetylation is induced by androgens and determines recruitment into

chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...

. The AR acetylation site is a key target of NAD-dependent and TSA-dependent

histone deacetylases Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...

and

long non-coding RNA Long non-coding RNAs (long ncRNAs, lncRNA) are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as mic ...

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 Steroid hormone receptors are found in the cell nucleus, nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid h ...

such as

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen ( 17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the ...

s, androgen receptors can have actions that are independent of their interactions with DNA. Androgen receptors interact with certain

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

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''

located on the

X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...

at Xq11–12.

Deficiencies

At least 165 disease-causing mutations in this gene have been discovered. The

, formerly known as testicular feminization, is caused by a mutation in the androgen receptor gene on the

(locus: Xq11–Xq12). The androgen receptor seems to affect neuron physiology and is defective in

Kennedy's disease Spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease, is a debilitating neurodegenerative disorder resulting in muscle cramps and progressive weakness due to degeneration of motor neurons in the brainstem and spinal c ...

. In addition,

point mutations A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...

and trinucleotide repeat polymorphisms have been linked to a number of additional disorders.

CAG repeats

The AR gene contains

CAG repeats Trinucleotide repeat disorders, also known as microsatellite expansion diseases, are a set of over 50 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides ( trinucleotide repeats) inc ...

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, with African-Americans having fewer repeats than non-Hispanic white Americans. The racial trends in CAG repeats parallels the incidence and mortality of prostate cancer in these groups.

Structure

Isoforms

Two

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

of the androgen receptor (A and B) have been identified: * AR-A – 87

kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...

;

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

truncated (lacks the first 187

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

), which results from ''in vitro''

proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...

. * 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: * A/B) – N-terminal regulatory domain contains: ** activation function 1 (AF-1) between residues 101 and 370 required for full

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

-activated transcriptional activity ** activation function 5 (AF-5) between residues 360–485 is responsible for the

constitutive activity In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a recepto ...

(activity without bound ligand) ** dimerization surface involving residues 1–36 (containing the FXXLF motif; where F =

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

, L =

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...

, and X = any amino acid residue) and 370–494, both of which interact with the ligand binding domain (LBD) in an intramolecular head-to-tail interaction * C) –

DNA binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a genera ...

(DBD) * D) – Hinge region; flexible region that connects the DBD with the LBD; along with the DBD, contains a ligand dependent

nuclear localization signal A nuclear localization signal ''or'' sequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines o ...

* 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 A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA p ...

proteins (containing the LXXLL or preferably FXXFL motifs) ** A ligand dependent

nuclear export signal A nuclear export signal (NES) is a short target peptide containing 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite ...

* F) –

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

domain

Splice variants

AR-V7 is an androgen receptor

splice variant Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...

that can be detected in

circulating tumor cell A circulating tumor cell (CTC) is a cell that has shed into the vasculature or lymphatics from a primary tumor and is carried around the body in the blood circulation. CTCs can extravasate and become ''seeds'' for the subsequent growth of additional ...

s of metastatic

patients and is predictive of resistance to some drugs.

Clinical significance

High expression in androgen receptor has been linked to aggression and sex drive by affecting the HPA and HPG axis Aberrant androgen receptor coregulator activity may contribute to the progression of

Ligands

Agonists

Endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

s (e.g.,

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroepia ...

androstenediol Androstenediol, or 5-androstenediol (abbreviated as A5 or Δ5-diol), also known as androst-5-ene-3β,17β-diol, is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepiand ...

dehydroepiandrosterone Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It functio ...

) * Synthetic

s (e.g.,

methyltestosterone Methyltestosterone, sold under the brand names Android, Metandren, and Testred among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, at low ...

metandienone Metandienone, also known as methandienone or methandrostenolone and sold under the brand name Dianabol (D-Bol) among others, is an androgen and anabolic steroid (AAS) medication which is still quite often used because of its affordability and eff ...

nandrolone Nandrolone, also known as 19-nortestosterone, is an androgen and anabolic steroid (AAS) which is used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionate (brand name Durabolin). Nandrolon ...

trenbolone Trenbolone is an androgen and anabolic steroid (AAS) of the nandrolone group which itself was never marketed. Trenbolone ester prodrugs, including trenbolone acetate (brand names Finajet, Finaplix, others) and trenbolone hexahydrobenzylcarbonate ...

oxandrolone Oxandrolone, sold under the brand names Oxandrin and Anavar, among others, is an androgen and anabolic steroid (AAS) medication which is used to help promote weight gain in various situations, to help offset protein catabolism caused by long-term ...

stanozolol Stanozolol (Abbreviation, abbrev. Stz), sold under many brand names, is an androgen and anabolic steroid (AAS) medication derived from dihydrotestosterone (DHT). It is used to treat hereditary angioedema. It was developed by American pharmaceuti ...

)

Mixed

Selective androgen receptor modulator Selective Androgen Receptor Modulators or SARMs are a class of androgen receptor ligands that maintain some of the desirable effects of androgens, such as preventing osteoporosis and muscle loss while reducing risks of developing prostate cancer ...

s (e.g.,

andarine Andarine (developmental code names GTx-007, S-4) is an investigational selective androgen receptor modulator (SARM) developed by GTX, Inc for treatment of conditions such as muscle wasting, osteoporosis and benign prostatic hypertrophy, using th ...

enobosarm Enobosarm, also known as ostarine or MK-2866, is an investigational selective androgen receptor modulator (SARM) developed by GTx, Inc. for the treatment of conditions such as muscle wasting and osteoporosis, formerly under development by Merc ...

)

Antagonists

Steroidal antiandrogen A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) ...

s (e.g.,

cyproterone acetate Cyproterone acetate (CPA), sold alone under the brand name Androcur or Ethinylestradiol/cyproterone acetate, with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treat ...

chlormadinone acetate Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hor ...

spironolactone Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure ...

oxendolone Oxendolone, sold under the brand names Prostetin and Roxenone, is an antiandrogen and progestin medication which is used in Japan in the treatment of enlarged prostate. However, this use is controversial due to concerns about its clinical effic ...

) *

Nonsteroidal antiandrogen A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like t ...

s (e.g.,

flutamide Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growt ...

nilutamide Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer.https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020169s008lbl.pdf It has also been ...

bicalutamide Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical remo ...

enzalutamide Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castrat ...

apalutamide Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatme ...

RU-58841 __NOTOC__ RU-58841, also known as PSK-3841 or HMR-3841, is a nonsteroidal antiandrogen (NSAA) which was initially developed in the 1980s by Roussel Uclaf, the French pharmaceutical company from which it received its name. It was formerly under inv ...

) *

N-Terminal domain antiandrogen ''N''-Terminal domain antiandrogens are a novel type of antiandrogen that bind to the ''N''-terminal domain of the androgen receptor (AR) instead of the ligand-binding domain (where all currently-available antiandrogens bind) and disrupt inte ...

s (e.g.,

bisphenol A Bisphenol A (BPA) is a chemical compound primarily used in the manufacturing of various plastics. It is a colourless solid which is soluble in most common organic solvents, but has very poor solubility in water. BPA is produced on an industrial s ...

EPI-001 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 ...

ralaniten Ralaniten (developmental code name EPI-002) is an N-terminal domain antiandrogen which was never marketed. It is a derivative (chemistry), derivative of bisphenol A and one of the four stereoisomers of EPI-001. A prodrug of ralaniten, ralaniten ac ...

, JN compounds)

As a drug target

The AR is an important therapeutic target in

. Thus many different

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the ...

s have been developed, primarily targeting the

ligand-binding domain In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

of the protein. AR

ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...

can either be classified based on their structure (

steroidal A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mod ...

) or based on their ability to activate or inhibit transcription (

agonists An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an ...

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

s). Inhibitors that target alternative functional domains (

N-terminal domain The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

DNA-binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a genera ...

) of the protein are still under development.

Interactions

Androgen receptor has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: *

AKT1 RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It i ...

, *

BAG1 BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the ''BAG1'' gene. Function The oncogene BCL2 is a membrane protein that blocks a step in a pathway leading to apoptosis or programmed cell death. The protein ...

, *

Beta-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...

, *

BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...

, *

C-jun 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 lat ...

, *

Calmodulin 1 Calmodulin 1 is a protein that in humans is encoded by the ''CALM1'' gene. Function Calmodulin 1 is the archetype of the family of calcium-modulated (calmodulin) proteins of which nearly 20 members have been found. They are identified by their ...

, *

Caveolin 1 Caveolin-1 is a protein that in humans is encoded by the ''CAV1'' gene. Function The scaffolding protein encoded by this gene is the main component of the caveolae plasma membranes found in most cell types. The protein links integrin subunits ...

, *

CDK9 Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb. Function The protein encoded by this gene is a member of the cyclin-dependent kinase (CDK) family. CDK family members are highly similar to the gene produ ...

, *

COX5B Cytochrome ''c'' oxidase subunit 5B, mitochondrial is an enzyme in humans that is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. In humans, cytochrome c oxid ...

, *

CREB-binding protein Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intrin ...

, *

Cyclin D1 Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...

, *

Cyclin-dependent kinase 7 Cyclin-dependent kinase 7, or cell division protein kinase 7, is an enzyme that in humans is encoded by the ''CDK7'' gene. The protein encoded by this gene is a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are h ...

, *

DACH1 Dachshund homolog 1, also known as DACH1, is a protein which in humans is encoded by the ''DACH1'' gene. DACH1 has been shown to interact with Ubc9, Smad4, and NCoR. Structure Gene structure . This protein coding gene has 760 amino acid protei ...

, *

Death associated protein 6 Death-associated protein 6 also known as Daxx is a protein that in humans is encoded by the ''DAXX'' gene. Function Daxx, a Death domain-associated protein, was first discovered through its cytoplasmic interaction with the classical death rece ...

, *

L-DOPA -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

, *

EFCAB6 EF-hand calcium-binding domain-containing protein 6 is a protein that in humans is encoded by the ''EFCAB6'' gene. Interactions EFCAB6 has been shown to interact with PARK7 and Androgen receptor The androgen receptor (AR), also known as NR ...

, *

Epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor recept ...

, *

FOXO1 Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the ''FOXO1'' gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glyco ...

, *

GAPDH Glyceraldehyde 3-phosphate dehydrogenase (abbreviated GAPDH) () is an enzyme of about 37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. In addition to this long establishe ...

, *

Gelsolin Gelsolin is an actin-binding protein that is a key regulator of actin filament assembly and disassembly. Gelsolin is one of the most potent members of the actin-severing gelsolin/villin superfamily, as it severs with nearly 100% efficiency. Cellu ...

, *

GNB2L1 Receptor for activated C kinase 1 (RACK1), also known as guanine nucleotide-binding protein subunit beta-2-like 1 (GNB2L1), is a 35 kDa protein that in humans is encoded by the RACK1 gene. Function RACK1 was originally isolated and identified a ...

, *

GSK3B Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the ''GSK3B'' gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased suscept ...

, *

HDAC1 Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene. Function Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. T ...

, *

HSP90AA1 Heat shock protein HSP 90-alpha is a protein that in humans is encoded by the ''HSP90AA1'' gene. Function The gene, HSP90AA1, encodes the human stress-inducible 90-kDa heat shock protein alpha (Hsp90A). Complemented by the constitutively expr ...

, *

HTATIP Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the ''KAT5'' gene. It is also commonly identified as TIP60. The protein encoded by this gene belongs to the MYST family of histone acetyl transferases (HATs) and was origina ...

, *

MAGEA11 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. MAGEA11 is an androgen coregulator specific to primates. It was first ...

, *

MED1 Mediator of RNA polymerase II transcription subunit 1 also known as DRIP205 or Trap220 is a subunit of the Mediator complex and is a protein that in humans is encoded by the ''MED1'' gene. MED1 functions as a nuclear receptor coactivator. Func ...

, *

MYST2 Histone acetyltransferase KAT7 is an enzyme that in humans is encoded by the ''KAT7'' gene. It specifically acetylates H4 histones at the lysine12 residue (H4K12) and is necessary for origin licensing and DNA replication. KAT7 associates with o ...

, *

NCOA1 The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by ...

, *

NCOA2 NCOA may refer to: *National Change Of Address database (see United States Postal Service) *National Chamber Orchestra of Armenia *National Council on Aging * The Non-commissioned officer, Noncomissioned Officer Academy in the United States Air For ...

, *

NCOA3 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 recept ...

, *

NCOA4 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 hea ...

, *

NCOA6 Nuclear receptor coactivator 6 is a protein that in humans is encoded by the ''NCOA6'' gene. Function The protein encoded by this gene is a transcriptional coactivator that can interact with nuclear hormone receptors to enhance their transcrip ...

, * NCOR2, *

NONO Nono may refer to: Places * Nono, Argentina, a municipality in the Province of Córdoba * Nono, Ecuador, a parish in the municipality of Quito in the province of Pichincha * Nono, Illubabor, Oromia (woreda), Ethiopia, or Nono Sele ** Nono, Illub ...

, * p300, * PA2G4, *

PAK6 Serine/threonine-protein kinase PAK 6 is an enzyme that in humans is encoded by the ''PAK6'' gene. PAK6 belongs to the Group II PAK family members. Like other family members, PAK6 is also evolutionary conserved across species. Discovery The PAK ...

, *

PATZ1 POZ-, AT hook-, and zinc finger-containing protein 1 is a protein that in humans is encoded by the ''PATZ1'' gene. Function The protein encoded by this gene contains an AT-hook DNA binding motif, which usually binds to other DNA binding struc ...

, *

PIAS2 E3 SUMO-protein ligase PIAS2 is an enzyme that in humans is encoded by the ''PIAS2'' gene. Interactions Protein inhibitor of activated STAT2 has been shown to interact with: * Androgen receptor, * DNMT3A, * PARK7, and * UBE2I SUMO-conjugat ...

, *

PRPF6 Pre-mRNA-processing factor 6 is a protein that in humans is encoded by the ''PRPF6'' gene. The protein encoded by this gene appears to be involved in pre-mRNA splicing, possibly acting as a bridging factor between U5 and U4/U6 snRNPs in formation ...

, * PTEN, *

RAD9A Cell cycle checkpoint control protein RAD9A is a protein that in humans is encoded by the ''RAD9A'' gene.''Rad9'' has been shown to induce G2 arrest in the cell cycle in response to DNA damage in yeast cells. ''Rad9'' was originally found in buddin ...

, *

RANBP9 Ran-binding protein 9 is a protein that in humans is encoded by the ''RANBP9'' gene. Function This gene encodes a protein that binds RAN, a small GTP binding protein belonging to the RAS superfamily that is essential for the translocation of RN ...

, * RCHY1, *

Retinoblastoma protein The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...

, *

RNF14 E3 ubiquitin-protein ligase RNF14 is an enzyme that in humans is encoded by the ''RNF14'' gene. Function The protein encoded by this gene contains a RING zinc finger, a motif known to be involved in protein-protein interactions. This protein i ...

, *

RNF4 RING finger protein 4 is a protein that in humans is encoded by the ''RNF4'' gene. The protein encoded by this gene contains a RING finger domain and acts as a transcription factor. This protein has been shown to interact with, and inhibit the ac ...

, *

SART3 Squamous cell carcinoma antigen recognized by T-cells 3 is a protein that in humans is encoded by the ''SART3'' gene. The protein encoded by this gene is an RNA-binding nuclear protein that is a tumor-rejection antigen. This antigen possesses tumo ...

, *

SIRT1 Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene. SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (''S. cerevisiae''), referring to the fact t ...

, *

SMAD3 Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene. SMAD3 is a member of the SMAD family of proteins. It acts as a mediator of the signals initiated by t ...

, *

Small heterodimer partner The small heterodimer partner (SHP) also known as NR0B2 (nuclear receptor subfamily 0, group B, member 2) is a protein that in humans is encoded by the ''NR0B2'' gene. SHP is a member of the nuclear receptor family of intracellular transcription ...

, * Src, * SRY, *

STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respons ...

, * SVIL, *

Testicular receptor 2 The testicular receptor 2 (TR2) also known as NR2C1 (nuclear receptor subfamily 2, group C, member 1) is protein that in humans is encoded by the ''NR2C1'' gene. TR2 is a member of the nuclear receptor family of transcription factors. Interactio ...

, *

Testicular receptor 4 Testicular receptor 4 also known as NR2C2 (nuclear receptor subfamily 2, group C, member 2) is a protein that in humans is encoded by the ''NR2C2'' gene. The testicular receptor 4 is a member of the nuclear receptor family of transcription factor ...

, *

TGFB1I1 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 ( Hydrogen Peroxide-Inducible Clone ...

, * TMF1, * TRIM68, *

UBE2I SUMO-conjugating enzyme UBC9 is an enzyme that in humans is encoded by the ''UBE2I'' gene. It is also sometimes referred to as "ubiquitin conjugating enzyme E2I" or "ubiquitin carrier protein 9", even though these names do not accurately describe ...

, *

UXT Protein UXT (Ubiquitously eXpressed Transcript protein) also known as androgen receptor trapped clone 27 (ART-27) protein is a protein that in humans is encoded by the ''UXT'' gene. Function UXT interacts with the N-terminus of the androgen re ...

, and *

ZMIZ1 Zinc finger MIZ domain-containing protein 1 is a protein that in humans is encoded by the ''ZMIZ1'' gene. Interactions ZMIZ1 has been shown to interact with Androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear recepto ...

References

External links

GeneReviews/NCBI/NIH/UW entry on Androgen Insensitivity Syndrome

OMIM entries on Androgen Insensitivity Syndrome

GeneReviews/NIH/NCBI/UW entry on Spinal and Bulbar Muscular Atrophy, Kennedy's Disease, SBMA, X-Linked Spinal and Bulbar Muscular Atrophy

OMIM entries on Spinal and Bulbar Muscular Atrophy, Kennedy's Disease, SBMA, X-Linked Spinal and Bulbar Muscular Atrophy
* * * * * * * {{DEFAULTSORT:Androgen Receptor Genes on human chromosome X 3

Function

Effect on development

Maintenance of male skeletal integrity

Role in females

Mechanism of action

Genomic

Non-genomic

Genetics

Gene

Deficiencies

CAG repeats

Structure

Isoforms

Domains

Splice variants

Clinical significance

Ligands

Agonists

Mixed

Antagonists

As a drug target

Interactions

See also

References

External links