Nerve Growth factor IB
Encyclopedia
The nerve Growth factor IB (NGFIB) also known as Nur77 or NR4A1 (nuclear receptor subfamily 4 group A member 1) is a protein
that in humans is encoded by the NR4A1 gene
.
Nerve Growth factor IB is a member of the Nur
nuclear receptor
family of intracellular
transcription factor
s. NGFIB is involved in cell cycle
mediation, inflammation
and apoptosis
.
The NGFIB protein plays a key role in mediating inflammatory
responses in macrophage
s. In addition, subcellular localization of the NGFIB protein appears to play a key role in the survival and death of cells.
Expression is induced by phytohemagglutinin in human lymphocytes and by serum stimulation of arrested fibroblasts. Translocation of the protein from the nucleus to mitochondria induces apoptosis. Multiple alternatively spliced variants, encoding the same protein, have been identified.
s. An amino terminal transactivation
domain is encoded in exon 2, a DNA-binding domain
in exons 3 and 4, and dimerisation and ligand-binding domains is exons 5 to 7.
The protein has an atypical ligand-binding domain that is unlike the classical ligand-binding domain in most nuclear receptors. The classical domain contains a ligand-receiving pocket and co-activator site, both of which are lacking in the NR4A family. Where most nuclear receptors have a hydrophobic surface that results in a cleft, NGFI-B has a hydrophilic surface.
Cofactors interact with NGFI-B at a hydrophobic region between helices 11 and 12 to modulate transcription.
family members, NGFIB is expressed in macrophages following inflammatory stimuli. This process is mediated by the NF-κB (nuclear factor-kappa B) complex, a ubiquitous transcription factor
involved in cellular response to stress.
NGFIB can be induced by many physiological and physical stimuli. These include physiological stimuli such as "fatty acids, stress, prostaglandins, growth factors, calcium, inflammatory cytokines, peptide hormones, phorbol esters, and neurotransmitters" and physical stimuli including "magnetic fields, mechanical agitation (causing fluid shear stress), and membrane depolarization". Ligands do not bind to NGFIB, so modulation occurs at the level of protein expression and posttranslational modification.
or homodimer to response element
NBRE and as a homodimer to NurRE. It is also capable of heterodimerising with COUP-TF (an orphan nuclear receptor) and retinoid X receptor
(RXR) in mediating transcription in response to retinoid
s.
The binding site
s on the response elements for NGFI-B, which are common to the two other members of the Nur
family, are :
gene symbol NR4A1. It belongs to a group of three closely related orphan receptors, the Nur
family, which has the symbol NR4A. The other two members are nuclear receptor related 1 protein
(denoted by symbol NR4A2) and neuron-derived orphan receptor 1
(NR4A3).
NGFIB has a high degree of structural similarity with other family members at the DNA-binding domain with 91-95% sequence conservation
. The C-terminal ligand-binding domain is conserved to a lesser extent at 60% and the N-terminal AB region is not conserved, differing in each member.
The three members are similar in biochemistry and function. They are immediate early gene
s activated in a ligand-independent manner that bind at the same sites on response elements.
NGFIB and the rest of the Nur family are structurally similar to other nuclear receptor
superfamily members, but contain an extra intron
. The DNA-binding domain at exons 3 and 4 of the NR4A1 gene is conserved among all members of the nuclear receptor.
NR4A1 has homologous
genes in a range of species including neuronal growth factor-induced clone B in rat
s, Nur77 in mice
and TR3 in human
s.
of some primary solid tumours. It is downregulated in this process.
with:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the NR4A1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Nerve Growth factor IB is a member of the Nur
Nur (biology)
Nur is a family of orphan nuclear receptors which act as transcription factors in neuron development and maintenance...
nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
family of intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s. NGFIB is involved in cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
mediation, inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
The NGFIB protein plays a key role in mediating inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
responses in macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s. In addition, subcellular localization of the NGFIB protein appears to play a key role in the survival and death of cells.
Expression is induced by phytohemagglutinin in human lymphocytes and by serum stimulation of arrested fibroblasts. Translocation of the protein from the nucleus to mitochondria induces apoptosis. Multiple alternatively spliced variants, encoding the same protein, have been identified.
Structure
The NR4A1 gene contains seven exonExon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s. An amino terminal transactivation
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
domain is encoded in exon 2, a DNA-binding domain
DNA-binding domain
A DNA-binding domain is an independently folded protein domain that 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...
in exons 3 and 4, and dimerisation and ligand-binding domains is exons 5 to 7.
The protein has an atypical ligand-binding domain that is unlike the classical ligand-binding domain in most nuclear receptors. The classical domain contains a ligand-receiving pocket and co-activator site, both of which are lacking in the NR4A family. Where most nuclear receptors have a hydrophobic surface that results in a cleft, NGFI-B has a hydrophilic surface.
Cofactors interact with NGFI-B at a hydrophobic region between helices 11 and 12 to modulate transcription.
Function
Along with the two other NurNur (biology)
Nur is a family of orphan nuclear receptors which act as transcription factors in neuron development and maintenance...
family members, NGFIB is expressed in macrophages following inflammatory stimuli. This process is mediated by the NF-κB (nuclear factor-kappa B) complex, a ubiquitous transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
involved in cellular response to stress.
NGFIB can be induced by many physiological and physical stimuli. These include physiological stimuli such as "fatty acids, stress, prostaglandins, growth factors, calcium, inflammatory cytokines, peptide hormones, phorbol esters, and neurotransmitters" and physical stimuli including "magnetic fields, mechanical agitation (causing fluid shear stress), and membrane depolarization". Ligands do not bind to NGFIB, so modulation occurs at the level of protein expression and posttranslational modification.
Biochemistry
Nerve Growth factor IB binds as a monomerMonomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
or homodimer to response element
Response element
Response elements are short sequences of DNA within a gene promoter region that are able to bind a specific transcription factor and regulate transcription of genes.-Examples:Examples of response elements include:*Hormone response element...
NBRE and as a homodimer to NurRE. It is also capable of heterodimerising with COUP-TF (an orphan nuclear receptor) and retinoid X receptor
Retinoid X receptor
The retinoid X receptor is a type of nuclear receptor that is activated by 9-cis retinoic acid. There are three retinoic X receptors : RXR-alpha, RXR-beta, and RXR-gamma, encoded by the , , genes, respectively....
(RXR) in mediating transcription in response to retinoid
Retinoid
The retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth....
s.
The binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
s on the response elements for NGFI-B, which are common to the two other members of the Nur
Nur (biology)
Nur is a family of orphan nuclear receptors which act as transcription factors in neuron development and maintenance...
family, are :
- NBRE - 5’-A/TAAAGGTCA,
- NurRE - a AAAT(G/A)(C/T)CA repeat,
- RXR - DX, a motifSequence motifIn genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance...
.
Evolution and homology
Nerve Growth factor IB has the systematic HUGOHuman Genome Organisation
The Human Genome Organisation is an organization involved in the Human Genome Project, a project about mapping the human genome. HUGO was established in 1989 as an international organization, primarily to foster collaboration between genome scientists around the world...
gene symbol NR4A1. It belongs to a group of three closely related orphan receptors, the Nur
Nur (biology)
Nur is a family of orphan nuclear receptors which act as transcription factors in neuron development and maintenance...
family, which has the symbol NR4A. The other two members are nuclear receptor related 1 protein
Nuclear receptor related 1 protein
The Nuclear receptor related 1 protein also known as NR4A2 is a protein that in humans is encoded by the NR4A2 gene. NURR1 is a member of the nuclear receptor family of intracellular transcription factors.NURR1 plays a key role in the maintenance of the dopaminergic system of the brain...
(denoted by symbol NR4A2) and neuron-derived orphan receptor 1
Neuron-derived orphan receptor 1
The neuron-derived orphan receptor 1 also known as NR4A3 is a protein that in humans is encoded by the NR4A3 gene...
(NR4A3).
NGFIB has a high degree of structural similarity with other family members at the DNA-binding domain with 91-95% sequence conservation
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...
. The C-terminal ligand-binding domain is conserved to a lesser extent at 60% and the N-terminal AB region is not conserved, differing in each member.
The three members are similar in biochemistry and function. They are immediate early gene
Immediate early gene
Immediate early genes are genes which are activated transiently and rapidly in response to a wide variety of cellular stimuli. They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli, before any new proteins are synthesized...
s activated in a ligand-independent manner that bind at the same sites on response elements.
NGFIB and the rest of the Nur family are structurally similar to other nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
superfamily members, but contain an extra intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
. The DNA-binding domain at exons 3 and 4 of the NR4A1 gene is conserved among all members of the nuclear receptor.
NR4A1 has homologous
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
genes in a range of species including neuronal growth factor-induced clone B in rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
s, Nur77 in mice
MICE
-Fiction:*Mice , alien species in The Hitchhiker's Guide to the Galaxy*The Mice -Acronyms:* "Meetings, Incentives, Conferencing, Exhibitions", facilities terminology for events...
and TR3 in human
Human
Humans are the only living species in the Homo genus...
s.
Pathology
Along with 16 other genes, Nerve Growth factor IB is a signature gene in the metastasisMetastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
of some primary solid tumours. It is downregulated in this process.
Interactions
Nerve Growth factor IB has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- AKT1AKT1RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for this gene.- Function :...
, - Bcl-2Bcl-2Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
, - HIF1AHIF1AHypoxia-inducible factor 1, alpha subunit , also known as HIF1A, is a protein that in humans is encoded by the HIF1A gene...
, - Nuclear receptor co-repressor 2Nuclear receptor co-repressor 2The nuclear receptor co-repressor 2 is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target...
, - Promyelocytic leukemia proteinPromyelocytic leukemia proteinProbable transcription factor PML is a tumor suppressor protein that in humans is encoded by the PML gene.-Interactions:Promyelocytic leukemia protein has been shown to interact with Retinoic acid receptor alpha, HDAC1, Nerve Growth factor IB, SKI protein, Zinc finger and BTB domain-containing...
, - Retinoid X receptor alphaRetinoid X receptor alphaRetinoid X receptor alpha , also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.- Function :...
, and - Von Hippel-Lindau tumor suppressorVon Hippel-Lindau tumor suppressorThe Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that in humans is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease....
.