Jun dimerization protein 2 (JUNDM2) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''JDP2''

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 ...

. The Jun dimerization protein is a member of the AP-1 family of

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. JDP 2 was found by a Sos-recruitment system, to dimerize with

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 ...

to repress AP-1-mediated activation. It was later identified by the yeast-two hybrid system to bind to activating transcription factor 2 (ATF2) to repress ATF-mediated transcriptional activation. JDP2 regulates

12-O-tetradecanoylphorbol-13-acetate 12-''O''-Tetradecanoylphorbol-13-acetate (TPA), also commonly known as tetradecanoylphorbol acetate, tetradecanoyl phorbol acetate, and phorbol 12-myristate 13-acetate (PMA) is a diester of phorbol. It is a potent Tumor promotion, tumor promoter ...

(TPA)

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 bi ...

(TRE)- and

cAMP Camp may refer to: Areas of confinement, imprisonment, or for execution * Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups * Extermination ...

-responsive element (CRE)-dependent transcription. The JDP2 gene is located on human chromosome 14q24.3 (46.4 kb, 75,427,715 bp to 75,474,111 bp) and mouse chromosome 12 (39 kb, 85,599,105 bp to 85,639,878 bp), which is located at about 250 kbp in the Fos-JDP2-BATF locus.

Alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

of JDP2 generates at least two

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

. The protein JDP2 has 163 amino acids, belongs to the family of basic leucine zipper (bZIP), and shows high homology with the ATF3 bZIP domain. The bZIP domain includes the amino acids from position 72 to 135, the basic motif from position 74 to 96, and the

leucine zipper A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amin ...

from 100 to 128. The molecular weight of the canonical JDP2 is 18,704 Da. The

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...

-binding region is located from position 35 to 72 and the inhibition of the

histone acetyltransferase Histone acetyltransferases (HATs) are enzymes that acetylation, acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine, ε-''N''-acetyllysine. DNA is wrapped around his ...

(INHAT) region is from position 35 to 135, which is located before the DNA-binding domain. JDP2 is expressed ubiquitously but is detected mainly in the

cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...

, brain, lung, and testis. A JDP2

single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

(SNP) was detected in Japanese, Korean, and Dutch cohorts, and is associated with an increased risk of

intracranial aneurysm An intracranial aneurysm, also known as a cerebral aneurysm, is a cerebrovascular disorder characterized by a localized dilation or ballooning of a blood vessel in the brain due to a weakness in the vessel wall. These aneurysms can occur in an ...

Posttranscriptional and post translational modifications

Phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

of the

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form when dissolved in water), a carboxyl group (which is in the deprotonated −COO− ...

(Thr) residue at position 148 is mediated by c-Jun N-terminal kinase ( MAPK8; JNK1) and p38 MAPK. Phosphorylated ATF2 inhibits the formation with JDP2 in vitro while phosphorylated JDP2 undergoes proteosomal degradation. It contains putative

SUMO is a form of competitive full-contact wrestling where a ''rikishi'' (wrestler) attempts to force his opponent out of a circular ring (''dohyō'') or into touching the ground with any body part other than the soles of his feet (usually by th ...

modification of

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...

(Lys) residue at position 65, and recruits interferon regulatory factor 2 binding protein 1 ( IRF2BP1), which acts as an E3 ligase. Phosphorylation of Thr at position 148 is detected in response to various stress conditions such as UV irradiation, oxidative stress, and anisomycin treatment or JDP2 is also regulated by other kinases such as p38 MAPK and doublecortin like protein kinase. Polyubiquitination of JDP2 protein is induced by IRF2BP1. JDP2 displays histone-binding and histone-chaperone activity. and inhibition of p300/CBP induced histone acetylation (INHAT). JDP2 recruits histone deacetylases

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. ...

and

HDAC2 Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the ''HDAC2'' gene. It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the ...

, HDAC6 and

HDAC3 Histone deacetylase 3 is an enzyme encoded by the ''HDAC3'' gene in both humans and mice. Function Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein comp ...

. JDP2 has INHAT activity and inhibits

histone methylation Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrea ...

in vitro.

Function

Phenotypes of gene knockout and transgenic mice

Gene

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

have a shorter tail, are smaller, have low

neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

count. and cell proliferation, and commit to cell cycle arrest because of AP-1 repression. TransgenicJDP2 mice display atrial dilation and myocardial hypertrophy.

Dimer formation and interacting molecules

JDP2 functions as a transcription activator 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 ...

depending on the leucine zipper protein member it is associated with. JDP2 forms a homodimer or heterodimer with

JUNB Transcription factor jun-B is a protein that, in humans, is encoded by the ''JUNB'' gene. Transcription factor jun-B is a transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a p ...

, JUND, Fra2, ATF2. and acts as a general repressor. On the other hand, JDP2 form a stable heterodimer with CHOP10 to enhance TRE- but not CRE-dependent transcription. In addition, JDP2 has been shown to directly associate with 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 resi ...

(PR) and functionally acts as a

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 ...

of progesterone-dependent PR-mediated gene transcription. Other proteins such as interferon regulatory factor-2-binding protein-1 ( IRF2BP1). CCAAT/enhancer-binding protein gamma (C/EBPγ),

and HDAC6 have also been demonstrated to associate with JDP2.

Cell differentiation

JDP2 plays a role in cell differentiation in several systems.

Ectopic expression Ectopic is a word used with a prefix ecto-, meaning “out of”, and the suffix -topic, meaning "place." Ectopic expression is an abnormal gene expression in a cell type, tissue type, or developmental stage in which the gene is not usually expresse ...

of JDP2 inhibits the

retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...

-induced differentiation of F9 cells and adipocyte differentiation. By contrast, JDP2 induces terminal muscle cell differentiation in C2 myoblasts and reduces the tumorigenicity of

rhabdomyosarcoma Rhabdomyosarcoma (RMS) is a highly aggressive form of cancer that develops from mesenchymal cells that have failed to fully differentiate into myocytes of skeletal muscle. Cells of the neoplasm, tumor are identified as rhabdomyoblasts. The four ...

cells and restored their ability to differentiate into myotubes. It is also reported that JDP2 plays an important role in the RANK-mediated osteoclast differentiation. Further, JDP2 is involved in neutrophil differentiation and transcription factor Tbx3-mediated osteoclastogenesis for host defense and bone homeostasis. Methylome mapping suggests that JDP2 plays a role in cell progenitor differentiation of

megakaryocyte A megakaryocyte () is a large bone marrow cell with a lobation, lobated nucleus that produces blood platelets (thrombocytes), which are necessary for normal blood coagulation, clotting. In humans, megakaryocytes usually account for 1 out of 10,00 ...

Regulation of cell cycle and p53 signaling

JDP2 induces

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 through

cyclin D Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S transition, G1/S phase transition. Cyclin D protein is anywhere fro ...

, p53, and cyclin A transcription, by increasing JUNB, JUND, and Fra2, and by decreasing c-JUN through the loss of p27^Kip1. JDP2 downregulates

p53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...

transcription, which promotes leukemogenesis. Mouse p53 protein negatively regulates the JDP2 promoter in F9 cells as part of the JDP2˗p53 autoregulatory circuit. By contrast, JDP2-knockout mice exhibit in downregulation of p53 and p21 proteins.

Apoptosis and senescence

JDP2 appears to be involved in the inhibition of

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 ...

. Depletion of JDP2 induces cell death similar to apoptosis. A study also demonstrated that UV irradiation induces JDP2 expression, which in turn down-regulates expression of p53 and thereby protects cells from UV-mediated programmed cell death. Heart-specific JDP2 overexpression protects cardiomyocytes against hypertrophic growth and TGFβ–induced apoptosis. In other settings, JDP2 has been shown to play an important role in the regulation of cellular

senescence Senescence () or biological aging is the gradual deterioration of Function (biology), functional characteristics in living organisms. Whole organism senescence involves an increase in mortality rate, death rates or a decrease in fecundity with ...

. JDP2-deficient mouse embryonic fibroblasts are resistant to replicative senescence by recruiting polycomb-repressive complexes (PRC1 and

PRC2 PRC2 (polycomb repressive complex 2) is one of the two classes of polycomb-group proteins or (PcG). The other component of this group of proteins is PRC1 ( Polycomb Repressive Complex 1). This complex has histone methyltransferase activity and ...

) to the promoters at the

p16Ink4a p16 (also known as p16INK4a, cyclin-dependent kinase inhibitor 2A, CDKN2A, multiple tumor suppressor 1 and numerous other synonyms), is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S ...

locus.

Oxidative stress and antioxidative response

The increased accumulation of intracellular

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 8-oxo-dGuo, one of the major products of DNA oxidation, and the reduced expression of several transcripts involved in ROS metabolism in Jdp2-deficient MEFs argue that JDP2 is required to hold ROS levels in check. Furthermore, JDP2 binds directly to the antioxidant responsive element (ARE) core sequence, associates with

Nrf2 Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regu ...

and

MafK #REDIRECT MAFK {{R from alternative capitalization ...

(Nrf2–MafK) via basic leucine zipper domains, and increases DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes such as HO1 and NQO1. Therefore, JDP2 functions as an integral component of the Nrf2–MafK complex to modulate antioxidant and detoxification programs.

Nuclear reprogramming

JDP2, which has been shown to regulate

Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...

and prevent ROS production, may play roles in cell reprogramming. Indeed, a study demonstrated that DAOY

medulloblastoma Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa. The brain is divided into two ...

cells can be reprogrammed successfully by JDP2 and the defined factor

OCT4 Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 ( POU domain, class 5, transcription factor 1), is a protein that in humans is encoded by the ''POU5F1'' gene. Oct-4 is a homeodomain transcription factor of the POU family ...

to become

induced pluripotent stem cell Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka and Kazutoshi Takahashi in Kyoto, Jap ...

s (iPSC)-like cells. This iPSC-like cells expressed stem cell-like characteristics including

alkaline phosphatase The enzyme alkaline phosphatase (ALP, alkaline phenyl phosphatase, also abbreviated PhoA) is a phosphatase with the physiological role of dephosphorylating compounds. The enzyme is found across a multitude of organisms, prokaryotes and eukaryo ...

activity and some stem cell markers, including SSEA3, SSEA4 and Tra-1-60. Later, another study also showed that JDP2 can substitute Oct4 to generate iPSCs with Klf4, Sox2 and

Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes r ...

(KSM) or KS from somatic cells. Moreover, they showed that JDP2 anchors five non-Yamanaka factors ( ID1, JHDM1B, LRH1,

SALL4 Sal-like protein 4 (SALL4) is a transcription factor encoded by a member of the ''Spalt-like'' (''SALL'') gene family, ''SALL4''. The ''SALL'' genes were identified based on their sequence homology to ''Spalt,'' which is a homeotic gene originally ...

, and GLIS1) to reprogram mouse embryonic fibroblasts into iPSCs.

Oncogene or tumor suppressor gene

JDP2 may act as a double-edge sword in

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...

. It is reported that JDP2 inhibits Ras-dependent cell transformation in NIH3T3 cells and tumor development in xenografts transplanted into SCID mice. Constitutive expression of JDP2 in

cells reduced their tumorigenic characteristics. On the other hand, JDP2 induces partial oncogenic transformation of chicken embryonic fibroblasts. Studies using high throughput viral insertional mutagenesis analysis also revealed that JDP2 functions as an oncogene. JDP2-transgenic mice display potentiation of liver cancer, higher mortality and increase number and size of tumors, especially when JDP2 expression is at the promotion stage.

Cancer and disease markers

JDP2 shows the gene amplification of head and neck squamous-cell carcinoma. In pancreatic carcinoma, downregulation of JDP2 is correlated with lymph node metastasis and distant metastasis and strongly associated with the post-surgery survival time, indicating that JDP2 may serve as a

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

to predict the prognosis of patients with pancreatic cancer. In addition, JDP2 overexpression reverses the epithelial-to-mesenchymal transition (EMT) induced by co-treatment with TGF-β1 and EGF in human pancreatic BxPC-3 cells, suggesting that JDP2 may be a molecular target for pancreatic carcinoma intervention. Furthermore, it has been shown that the expression level of JDP2 gene upon acute

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

(AMI) is highly specific and a sensitive biomarker for predicting heart failure. In T cell acute lymphoblastic leukaemia, JDP2 regulates pro-survival signalling through direct transcriptional regulation of MCL1 and leads to steroid resistance in vivo.

JDP2 targets and JDP2-regulated genes

JDP2 is involved in the modulation of gene expression. For example, JDP2 regulates

MyoD MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins kn ...

gene expression with c-Jun and gene for galectin-7. JDP2 functionally associated with HDAC3 and acts as a repressor to inhibit the amino acid regulation of CHOP transcription. JDP2 and ATF3 are involved in recruiting HDACs to the ATF3 promoter region resulting in transcriptional repression of ATF3. JDP2 inhibits the promoter of the Epstein–Barr virus (EBV) immediate early gene BZLF1 for the regulation of the latent-lytic switch in EBV infection.