The
glucocorticoid receptor (
GR, or GCR) also known as
NR3C1 (
nuclear receptorIn the field of molecular biology, nuclear receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of steroid and thyroid hormones and certain other molecules...
subfamily 3, group C, member 1) is the receptor that
cortisolCortisol is a corticosteroid hormone or glucocorticoid produced by the adrenal cortex, that is part of the adrenal gland . It is usually referred to as the "stress hormone" as it is involved in response to stress and anxiety, controlled by CRH...
and other glucocorticoids bind to.
The GR is expressed in almost every cell in the body and regulates
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
s controlling the
developmentDevelopmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis," which is the process that gives rise to tissues, organs and anatomy.Developmental biology is that...
,
metabolismMetabolism is the set of chemical reactions that occur in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter,...
, and
immune responseAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumour cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Because the receptor gene is expressed in several forms, it has many different (pleiotropic) effects in different parts of the body.
When the GR binds to glucorticoids, its primary mechanism of action is the regulation of gene transcription.
The
glucocorticoid receptor (
GR, or GCR) also known as
NR3C1 (
nuclear receptorIn the field of molecular biology, nuclear receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of steroid and thyroid hormones and certain other molecules...
subfamily 3, group C, member 1) is the receptor that
cortisolCortisol is a corticosteroid hormone or glucocorticoid produced by the adrenal cortex, that is part of the adrenal gland . It is usually referred to as the "stress hormone" as it is involved in response to stress and anxiety, controlled by CRH...
and other glucocorticoids bind to.
The GR is expressed in almost every cell in the body and regulates
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
s controlling the
developmentDevelopmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis," which is the process that gives rise to tissues, organs and anatomy.Developmental biology is that...
,
metabolismMetabolism is the set of chemical reactions that occur in living organisms to maintain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter,...
, and
immune responseAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumour cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Because the receptor gene is expressed in several forms, it has many different (pleiotropic) effects in different parts of the body.
When the GR binds to glucorticoids, its primary mechanism of action is the regulation of gene transcription. The unbound receptor resides in the
cytosolThe cytosol or intracellular fluid is the liquid found inside cells. In eukaryotes this liquid is separated by cell membranes from the contents of the organelles suspended in the cytosol, such as the mitochondrial matrix inside the mitochondrion...
of the cell (the part of the cell outside of the
nucleusIn cell biology, the nucleus , also sometimes referred to as the "control center", is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as...
). After the receptor is bound to glucocorticoid, the receptor-glucorticoid complex can take either of two paths. The activated GR complex up-regulates the expression of anti-inflammatory proteins in the nucleus or represses the expression of pro-inflammatory proteins in the cytosol (by preventing the translocation of other
transcription factorIn the field of molecular biology, a transcription factor is a protein that binds to specific DNA sequences and thereby controls the transfer of genetic information from DNA to mRNA...
s from the cytosol into the nucleus).
The GR protein is encoded by
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
on
chromosome 5125px|rightChromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs and represents almost 6% of the total DNA in cells. Chromosome 5 is one of the largest human chromosomes, yet has one of the...
(5q31).
Structure
Like the other steroid receptors, the glucocorticoid receptor is modular in structure and contains the following domains (labeled
A -
F):
- A/B - N-terminal regulatory domain
- C - DNA-binding domain
DNA-binding domain refers to an independently folded protein domain, which contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
(DBD)
- D - hinge region
- E - ligand-binding domain (LBD)
- F - C-terminal domain
Ligand binding and response
In the absence of hormone, the glucocorticoid receptor (GR) resides in the cytosol complexed with a variety of proteins including heat shock protein 90 (
hsp90Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family which is upregulated in response to stress...
), the heat shock protein 70 (
hsp70The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...
) and the protein
FKBP52FK506-binding protein 4 is a protein that in humans is encoded by the FKBP4 gene.This protein has TPR domain and PPlase domain.-Further reading:-External links:...
(FK506-binding protein 52). The endogenous glucocortiod hormone
cortisolCortisol is a corticosteroid hormone or glucocorticoid produced by the adrenal cortex, that is part of the adrenal gland . It is usually referred to as the "stress hormone" as it is involved in response to stress and anxiety, controlled by CRH...
diffuses through the cell membrane into the cytoplasm and binds to the glucocorticoid receptor (GR) resulting in release of the heat shock proteins. The resulting activated form GR has two principal mechanisms of action, transactivation and transrepression, described below.
Transactivation
A direct mechanism of action involves homodimerization of the receptor, translocation via active transport into the
nucleusIn cell biology, the nucleus , also sometimes referred to as the "control center", is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as...
, and binding to specific DNA responsive elements activating gene
transcriptionTranscription, or RNA synthesis, is the process of creating an equivalent RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA in the presence of the correct enzymes...
. This mechanism of action is referred to as
transactivationTransactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
. The biologic response depends on the cell type.
Transrepression
In the absence of activated GR, other transcription factors such as
NF-κBNF-κB is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens...
or
AP-1In the field of molecular biology, the activator protein 1 is a transcription factor which is a heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families. It regulates gene expression in response to a variety of stimuli, including cytokines, growth factors,...
themselves are able to transactivate target genes. However activated GR can complex with these other transcription factors and prevent them from binding their target genes and hence repress the expression of genes that are normally upregulated by NF-κB or AP-1. This indirect mechanism of action is referred to as
transrepressionIn the field of molecular biology, transrepression is a process whereby one protein represses the activity of a second protein through a protein-protein interaction...
.
Agonists and antagonists
DexamethasoneDexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones. It acts as an anti-inflammatory and immunosuppressant...
is an agonist, and RU486 and
cyproteroneCyproterone acetate is an antiandrogen, i.e. it suppresses the actions of testosterone on tissues...
are antagonists of the GR. Also,
progesteroneProgesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
and DHEA have antagonist effects on the GR.
Interactions
Glucocorticoid receptor has been shown to
interactProtein-protein interactions involve not only the direct-contact association of protein molecules but also longer range interactions through the electrolyte, aqueous solution medium surrounding neighbor hydrated proteins over distances from less than one nanometer to distances of several tens of...
with
ThioredoxinThioredoxin is an enzyme that, in humans, is encoded by the TXN gene.- Function :Thioredoxins are proteins that act as antioxidants by facilitating the reduction of other proteins by cysteine thiol-disulfide exchange...
,
MED14Mediator of RNA polymerase II transcription subunit 14 is an enzyme that in humans is encoded by the MED14 gene.-Interactions:MED14 has been shown to interact with PPARGC1A, Estrogen receptor alpha, STAT2, Cyclin-dependent kinase 8, Glucocorticoid receptor and Hepatocyte nuclear factor 4...
,
CREB binding proteinCREB-binding protein , also known as CREBBP or CBP, is a protein that, in humans, is encoded by the CREBBP gene.- Function :...
,
Nuclear receptor coactivator 2The nuclear receptor coactivator 2 is a transcriptional coregulatory protein which contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA2 is recruited to DNA promotion sites by ligand activated nuclear receptors. NCOA2 in turn acylates...
,
HNRPUHeterogeneous nuclear ribonucleoprotein U is a protein that in humans is encoded by the HNRNPU gene.-Interactions:HNRPU has been shown to interact with NDN, EP300, Glucocorticoid receptor and GTF2F1.-Further reading:...
,
POU2F1POU domain, class 2, transcription factor 1 is a protein that in humans is encoded by the POU2F1 gene.-Interactions:POU2F1 has been shown to interact with SNAPC4, Ku80, Glucocorticoid receptor, Sp1 transcription factor, NPAT, POU2AF1, Host cell factor C1, TATA binding protein, RELA, Nuclear...
,
STAT5BSignal transducer and activator of transcription 5B is a protein that in humans is encoded by the STAT5B gene.-Interactions:STAT5B has been shown to interact with PTPN11, Janus kinase 2, Janus kinase 1 and Glucocorticoid receptor.-Further reading:...
,
RELATranscription factor p65 is a protein that in humans is encoded by the RELA gene.-Interactions:RELA has been shown to interact with NFKBIB, ETHE1, NFKBIE, RFC1, TRIB3, CREB binding protein, Neutrophil cytosolic factor 1, Glucocorticoid receptor, MTPN, BRCA1, C-Fos, POU2F1, BTRC, TATA binding...
,
Nuclear receptor co-repressor 1The nuclear receptor co-repressor 1 is a transcriptional coregulatory protein which contains several nuclear receptor interacting domains. In addition, NCOR1 appears to recruit histone deacetylases to DNA promoter regions...
,
TRIM28Tripartite motif-containing 28 also known as transcriptional intermediary factor 1β is a protein which in humans is encoded by the TRIM24 gene.- Function :...
,
Nuclear receptor coactivator 3The nuclear receptor coactivator 3 also known as NCOA3 is a protein which in humans is encoded by the NCOA3 gene. NCOA3 is also frequently called amplified in breast 1 , steroid receptor coactivator-3 , or thyroid hormone receptor activator molecule 1 .-Function:NCOA3 is a transcriptional...
,
NRIP1Nuclear receptor-interacting protein 1 is a protein that in humans is encoded by the NRIP1 gene.Knockout mice that completely lack the RIP140 molecule are lean and stay lean, even on a rich diet...
,
CEBPBCCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the CEBPB gene.-Interactions:CEBPB has been shown to interact with CREB1, Sp1 transcription factor, Glucocorticoid receptor, Nucleolar phosphoprotein p130, DNA damage-inducible transcript 3, HSF1, RELA, Zif268, TRIM28,...
,
Mothers against decapentaplegic homolog 3SMAD family member 3, also known as SMAD3, is a human gene.SMAD3 or Mothers against decapentaplegic homolog 3 is a gene which appears in humans on chromosome 15...
,
Mineralocorticoid receptorThe mineralocorticoid receptor , also called aldosterone receptor, is officially labelled nuclear receptor subfamily 3, group C, member 2, and is a receptor with high affinity for mineralocorticoids...
,
Death associated protein 6Death associated protein 6 also known as DAXX is a protein which 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 receptor Fas...
,
STAT3Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
,
DAP328S ribosomal protein S29, mitochondrial is a protein that in humans is encoded by the DAP3 gene.-Interactions:DAP3 has been shown to interact with FADD, TNFRSF10A, Glucocorticoid receptor and Heat shock protein 90kDa alpha , member A1....
, Heat shock protein 90kDa alpha (cytosolic), member A1,
RANBP9Ran-binding protein 9 is a protein that in humans is encoded by the RANBP9 gene.-Interactions:RANBP9 has been shown to interact with C-Met, DYRK1B, USP11, DISC1, Androgen receptor, Glucocorticoid receptor, S100A7, HIPK2 and MKLN1.-Further reading:...
,
MED1Mediator of RNA polymerase II transcription subunit 1 is an enzyme that in humans is encoded by the MED1 gene.-Interactions:MED1 has been shown to interact with Thyroid hormone receptor alpha, Androgen receptor, Cyclin-dependent kinase 8, Glucocorticoid receptor, BRCA1, Hepatocyte nuclear factor 4...
,
Nuclear receptor coactivator 1The nuclear receptor coactivator 1 is a transcriptional coregulatory protein which contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity . NCOA1 is recruited to DNA promotion sites by ligand activated nuclear receptors. NCOA1 in turn acylates...
,
BAG1BAG family molecular chaperone regulator 1 is a protein that in humans is encoded by the BAG1 gene.BAG gene has been implicated in age related neurodegenerative diseases as Alzheimer's...
,
SMARCD1SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 is a protein that in humans is encoded by the SMARCD1 gene.-Interactions:SMARCD1 has been shown to interact with Glucocorticoid receptor.-Further reading:...
,
SMARCA4Probable global transcription activator SNF2L4 is a protein that in humans is encoded by the SMARCA4 gene.Recently a high percent of inactivation of this gene has been found in human lung cancer cell lines .-Interactions:...
and
YWHAH14-3-3 protein eta is a protein that in humans is encoded by the YWHAH gene.-Interactions:YWHAH has been shown to interact with TNFAIP3, KLC3, C-Raf, Phosphoinositide-dependent kinase-1, RIMS2, KIF5B, RIMS1, CDC25B, ZFP36, EPB41L3, Glucocorticoid receptor and TLX2.-Further reading:...
.
Further reading
See also
- Familial/sporadic glucocorticoid resistance (Chrousos Syndrome)
- Selective glucocorticoid receptor agonist
A selective glucocorticoid receptor agonist is a type of experimental drug which shares many of the desirable anti-inflammatory properties of classical glucocorticoid drugs but with fewer side effects such as skin atrophy...
(SEGRA)
External links