DNA damage-inducible transcript 3
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DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-
apoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes ( morphology) and death. These ...
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
that is encoded by the ''DDIT3''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming
heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...
s with other C/EBP members, preventing their DNA binding activity. The protein is implicated in
adipogenesis Adipogenesis is the formation of adipocytes (fat cells) from stem cells. It involves 2 phases, determination, and terminal differentiation. Determination is mesenchymal stem cells committing to the adipocyte precursor cells, also known as lipoblast ...
and
erythropoiesis Erythropoiesis (from Greek ''erythro'', meaning ''red'' and ''poiesis'', meaning ''to make'') is the process which produces red blood cells (erythrocytes), which is the development from erythropoietic stem cell to mature red blood cell. It is s ...
and has an important role in the cell's stress response.


Structure

C/EBP proteins are known to have a conserved
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy 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 t ...
structure, basic leucine zipper domain(bZIP), that is necessary for the formation of DNA-binding capable homodimers or heterodimers with other proteins or members of the C/EBP protein family. CHOP is a relatively small (29kDa) protein that differs from most C/EBP proteins in several amino acid substitutions, which impacts its DNA-binding ability.


Regulation and function

Due to a variety of upstream and downstream regulatory interactions, CHOP plays an important role in
ER stress The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms. The UPR is activated in response t ...
-induced
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
caused by a variety of stimuli such as pathogenic microbial or viral
infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
s, amino acid starvation, mitochondrial stress,
neurological diseases Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and ...
, and
neoplastic A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
diseases. Under normal physiological conditions, CHOP is ubiquitously present at very low levels. However, under overwhelming
ER stress The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms. The UPR is activated in response t ...
conditions, the expression of CHOP rises sharply along with the activation of apoptotic pathways in a wide variety of cells. Those processes are mainly regulated by three factors: protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring protein 1 (IRE1α)


Upstream regulatory pathways

During
ER stress The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms. The UPR is activated in response t ...
, CHOP is mainly induced via activation of the
integrated stress response The integrated stress response is a cellular stress response conserved in eukaryotic cells that downregulates protein synthesis and upregulates specific genes in response to internal or environmental stresses. Background The integrated stres ...
pathways through the subsequent downstream phosphorylation of a translation initiation factor, eukaryotic initiation factor 2α (eIF2α), and induction of a transcription factor, activation transcription factor 4 (
ATF4 Activating transcription factor 4 (tax-responsive enhancer element B67), also known as ATF4, is a protein that in humans is encoded by the ''ATF4'' gene. Function This gene encodes a transcription factor that was originally identified as a w ...
), which converges on the promoters of target genes, including CHOP. Integrated stress response, and thus CHOP expression, can be induced by * amino acid starvation through general control non-derepressible-2 (
GCN2 GCN2 (general control nonderepressible 2) is a serine/threonine-protein kinase that senses amino acid deficiency through binding to uncharged transfer RNA (tRNA). It plays a key role in modulating amino acid metabolism as a response to nutrient d ...
) * viral infection through the vertebrate-specific kinases - double-stranded RNA-activated protein kinase (PKR) * iron deficiency through
heme-regulated inhibitor kinase Eukaryotic translation initiation factor 2-alpha kinase 1 is an enzyme that in humans is encoded by the ''EIF2AK1'' gene. Function EIF2AK1 inhibits protein synthesis at the translation initiation level, in response to various stress conditions, ...
( HRI) * stress from the accumulation of unfolded or misfolded proteins in the ER activates the
integrated stress response The integrated stress response is a cellular stress response conserved in eukaryotic cells that downregulates protein synthesis and upregulates specific genes in response to internal or environmental stresses. Background The integrated stres ...
through protein kinase RNA-like endoplasmic reticulum kinase ( PERK). Under ER stress, activated transmembrane protein
ATF6 Activating transcription factor 6, also known as ATF6, is a protein that, in humans, is encoded by the ''ATF6'' gene and is involved in the unfolded protein response. Function ATF6 is an endoplasmic reticulum (ER) stress-regulated transmembr ...
translocates to the nucleus and interacts with ATF/cAMP response elements and ER stress-response elements, binding the promoters and inducing transcription of several genes involved in
unfolded protein response The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms. The UPR is activated in response t ...
(including CHOP,
XBP1 X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the ''XBP1'' gene. The ''XBP1'' gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5. The X ...
and others). Thus,
ATF6 Activating transcription factor 6, also known as ATF6, is a protein that, in humans, is encoded by the ''ATF6'' gene and is involved in the unfolded protein response. Function ATF6 is an endoplasmic reticulum (ER) stress-regulated transmembr ...
activates the transcription of both CHOP and XBP-1, while XBP-1 can also upregulate the expression of CHOP. ER stress also stimulates transmembrane protein IRE1α activity. Upon activation, IRE1α splices the XBP-1 mRNA introns to produce a mature and active XBP-1 protein, that upregulates CHOP expression IRE1α also stimulates the activation of the apoptotic-signaling kinase-1 (ASK1), which then activates the downstream kinases, Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase ( p38 MAPK), which participate in
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
induction along with CHOP. The P38 MAP kinase family phosphorylates Ser78 and Ser81 of CHOP, which induces cell apoptosis. Moreover, research studies found that the
JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are r ...
inhibitors can suppress CHOP upregulation, indicating that
JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are r ...
activation is also involved in the modulation of CHOP levels.


Downstream apoptotic pathways


Mitochondria-dependent

As a transcription factor, CHOP can regulate the expression of many anti-apoptotic and
pro-apoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
genes, including genes encoding the BCL2-family proteins, GADD34 and TRB-3. In the CHOP-induced apoptotic pathway, CHOP regulates the expression of BCL2 protein family, that includes anti-apoptotic proteins (
BCL2 Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the apoptosis regulator proteins, Bcl-2 family, Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can eithe ...
,
BCL-XL B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondr ...
,
MCL-1 Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the ''MCL1'' gene. Function The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two t ...
, and
BCL-W Bcl-2-like protein 2 is a 193-amino acid protein that in humans is encoded by the ''BCL2L2'' gene on chromosome 14 ( band q11.2-q12). It was originally discovered by Leonie Gibson, Suzanne Cory and colleagues at the Walter and Eliza Hall Instit ...
) and pro-apoptotic proteins (BAK, BAX, BOK,
BIM Building information modeling (BIM) is an approach involving the generation and management of digital representations of the physical and functional characteristics of buildings or other physical assets and facilities. BIM is supported by vario ...
, PUMA and others). Under ER stress, CHOP can function as either a
transcriptional activator A transcriptional activator is a protein (transcription factor) that increases transcription of a gene or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and ...
or
repressor In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
. It forms
heterodimers In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...
with other C/EBP family transcription factors via bZIP-domain interactions to inhibit the expression of genes responsive to C/EBP family transcription factors, while enhancing the expression of other genes containing a specific 12–14 bp DNA ''cis''-acting element. CHOP can
downregulate In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as R ...
the expressions of anti-apoptotic BCL2 proteins, and
upregulate In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as RNA ...
the expression of proapoptotic proteins (BIM, BAK and BAX expression). BAX-BAK oligomerization causes cytochrome c and apoptosis-inducing factor (AIF) release from mitochondria, eventually causing
cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as di ...
. TRB3 pseudokinase is upregulated by the ER stress-inducible transcriptional factor, ATF4-CHOP. CHOP interacts with TRB3, which contributes to the induction of apoptosis. The expression of TRB3 has a pro-apoptotic capacity. Therefore, CHOP also regulates apoptosis by upregulating the expression of the TRB3 gene.


Death-receptor dependent

Death receptor-mediated apoptosis occurs via activation of death ligands (Fas, TNF, and TRAIL) and death receptors. Upon activation, the receptor protein, Fas-associated death domain protein, forms a
death-inducing signaling complex The death-inducing signaling complex (DISC) is a multiprotein complex formed by members of the death receptor family of apoptosis-inducing cellular receptors. A typical example is FasR, which forms the DISC upon trimerization as a result of it ...
, which activates the downstream caspase cascade to induce
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
. The PERK-ATF4-CHOP pathway can induce
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
by binding to the death receptors and upregulating the expression of death receptor 4 (DR4) and DR5. CHOP also interacts with the phosphorylated transcription factor JUN to form a complex that binds to the promoter region of DR4 in lung cancer cells. The N-terminal domain of CHOP interacts with phosphorylated JUN to form a complex that regulates the expression of DR4 and DR5. CHOP also upregulates the expression of DR5 by binding to the 5′-region of the DR5 gene. Under prolonged ER stress conditions, activation of the PERK-CHOP pathway will permit DR5 protein levels to rise, which accelerates the formation of the
death-inducing signaling complex The death-inducing signaling complex (DISC) is a multiprotein complex formed by members of the death receptor family of apoptosis-inducing cellular receptors. A typical example is FasR, which forms the DISC upon trimerization as a result of it ...
(DISC) and activates
caspase-8 Caspase-8 is a caspase protein, encoded by the ''CASP8'' gene. It most likely acts upon caspase-3. ''CASP8'' orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present ...
, leading to
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...


Other downstream pathways

In addition, CHOP also mediates apoptosis through increasing the expression of the ERO1α (ER reductase) gene, which catalyzes the production of H2O2 in the ER. The highly oxidized state of the ER results in H2O2 leakage into the cytoplasm, inducing the production of
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
(ROS) and a series of apoptotic and inflammatory reactions. The overexpression of CHOP can lead to
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
arrest and result in cell apoptosis. At the same time, CHOP-induced apoptosis can also trigger cell death by inhibiting the expression of cell cycle regulatory protein, p21. The p21 protein inhibits the
G1 phase The G1 phase, gap 1 phase, or growth 1 phase, is the first of four phases of the cell cycle that takes place in eukaryotic cell division. In this part of interphase, the cell synthesizes Messenger RNA, mRNA and proteins in preparation for subsequ ...
of the cell cycle as well as regulates the activity of pre-apoptotic factors. Identified CHOP-p21 relationship may play a role in changing the cell state from adapting to ER stress towards pre-apoptotic activity. Under most conditions, CHOP can directly bind to the promoters of downstream related genes. However, under specific conditions, CHOP can cooperate with other
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s to affect apoptosis. Recent studies have shown that Bcl-2-associated athanogene 5 (Bag5) is over-expressed in
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
and inhibits ER stress-induced apoptosis. Overexpression of Bag5 results in decreased CHOP and BAX expression, and increased
Bcl-2 Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can either inhibit or induce it. It was the first a ...
gene expression. Bag5 overexpression inhibited ER stress-induced apoptosis in the
unfolded protein response The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms. The UPR is activated in response t ...
by suppressing PERK-
eIF2 Eukaryotic Initiation Factor 2 (eIF2) is a eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNAiMet to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer ...
-
ATF4 Activating transcription factor 4 (tax-responsive enhancer element B67), also known as ATF4, is a protein that in humans is encoded by the ''ATF4'' gene. Function This gene encodes a transcription factor that was originally identified as a w ...
and enhancing the IRE1-
Xbp1 X-box binding protein 1, also known as XBP1, is a protein which in humans is encoded by the ''XBP1'' gene. The ''XBP1'' gene is located on chromosome 22 while a closely related pseudogene has been identified and localized to chromosome 5. The X ...
activity. In general, the downstream targets of CHOP regulate the activation of apoptotic pathways, however, the molecular interaction mechanisms behind those processes remain to be discovered.


Interactions

DNA damage-inducible transcript 3 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...
with roteins * ATF3, *
C-Fos Protein c-Fos is a proto-oncogene that is the human homolog of the retroviral oncogene v-fos. It is encoded in humans by the ''FOS'' gene. It was first discovered in rat fibroblasts as the transforming gene of the FBJ MSV (Finkel–Biskis–Ji ...
, *
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 l ...
and *
CEBPB CCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the ''CEBPB'' gene. Function The protein encoded by this intronless gene is a bZIP transcription factor that can bind as a homodimer to certain DNA regulatory regi ...
, *
CSNK2A1 Casein kinase II subunit alpha is an enzyme that in humans is encoded by the ''CSNK2A1'' gene. Casein kinase II is a serine/threonine protein kinase that phosphorylates acidic proteins such as casein. The kinase exists as a tetramer and is co ...
, * JunD, and * RPS3A.


Clinical significance


Role in fatty liver and hyperinsulinemia

''Chop'' gene deletion has been demonstrated protective against diet induced metabolic syndromes in mice. Mice with germline ''Chop'' gene knockout have better glycemic control despite unchanged obesity. A plausible explanation for the observed dissociation between obesity and insulin resistance is that CHOP promotes insulin hypersecretion from pancreatic β cells. Furthermore, ''Chop'' depletion by a GLP1-ASO delivery system was shown to have therapeutic effects of insulin reduction and fatty liver correction, in preclinical mouse models.


Role in microbial infection

CHOP-induced apoptosis pathways had been identified in cells infected by * Porcine circovirus type 2 (PERK-eIF2α-ATF4 -CHOP-BCL2 pathway) *
HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
(XBP-1-CHOP-Caspase 3/9 pathway) *
Infectious bronchitis virus Infectious bronchitis virus (IBV) is a species of virus from the genus ''Gammacoronavirus'' that infects birds. It causes avian infectious bronchitis, a highly infectious disease that affects the respiratory tract, gut, kidney and reproductive ...
(PERK-eIF2α-ATF4/PKR-eIF2α-ATF4 pathway) * ''
M. tuberculosis ''Mycobacterium tuberculosis'' (M. tb), also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' ha ...
'' (PERK-eIF2α-CHOP pathway) * ''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, Flagellum#bacterial, flagellated, Bacterial cellular morphologies#Helical, helical bacterium. Mutants can have a rod or curved rod shape that exhibits l ...
'' (PERK-CHOP or PKR-eIF2α-ATF4 pathway) * ''
Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...
'' (CHOP-DR5-Caspase 3/8 pathway) * ''
Shigella dysenteriae ''Shigella dysenteriae'' is a species of the rod-shaped bacterial genus ''Shigella''. ''Shigella'' species can cause shigellosis ( bacillary dysentery). Shigellae are Gram-negative, non-spore-forming, facultatively anaerobic, nonmotile bacteri ...
'' (p38-CHOP-DR5 pathway) Since CHOP has an important role of apoptosis induction during infection, it is an important target for further research that will help deepen the current understanding of
pathogenesis In pathology, pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes . Descript ...
and potentially provide an opportunity for invention of new
therapeutic A therapy or medical treatment is the attempted remediation of a health problem, usually following a medical diagnosis. Both words, ''treatment'' and ''therapy'', are often abbreviated tx, Tx, or Tx. As a rule, each therapy has indications an ...
approaches. For example, small molecule inhibitors of CHOP expression may act as therapeutic options to prevent ER stress and microbial infections. Research had shown that small molecule inhibitors of PERK-eIF2α pathway limit PCV2 virus replication.


Role in other diseases

The regulation of CHOP expression plays an important role in metabolic diseases and in some cancers through its function in mediating apoptosis. The regulation of CHOP expression could be a potential approach to affecting cancer cells through the induction of apoptosis. In the intestinal epithelium, CHOP has been demonstrated to be downregulated under inflammatory conditions (in inflammatory bowel diseases and experimental models of colitis). In this context, CHOP seems to rather regulate the cell cycle than apoptotic processes. Mutations or fusions of CHOP (e.g. with FUS to form FUS-CHOP) can cause Myxoid liposarcoma.


References


Further reading

* * * * * * * * * * * * * * * * *


External links

* {{Transcription factors, g1 Transcription factors Oncogenes