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),[10][11] which is located at about 250 kbp in the Fos-JDP2-BATF locus.[12]Alternative splicing of JDP2 generates at least twoisoforms.[12][13] The protein JDP2 has 163 amino acids, belongs to the family ofbasic leucine zipper (bZIP), and shows high homology with theATF3 bZIP domain.[5][14] The bZIP domain includes the amino acids from position 72 to 135, the basic motif from position 74 to 96, and theleucine zipper from 100 to 128. The molecular weight of the canonical JDP2 is 18,704 Da. Thehistone-binding region is located from position 35 to 72 and the inhibition of thehistone acetyltransferase (INHAT) region is from position 35 to 135,[15] which is located before the DNA-binding domain.
Phosphorylation of thethreonine (Thr) residue at position 148 is mediated by c-Jun N-terminal kinase (MAPK8;JNK1) andp38 MAPK.[19][20] Phosphorylated ATF2 inhibits the formation with JDP2 in vitro[21] while phosphorylated JDP2 undergoes proteosomal degradation.[22] It contains putativeSUMO modification oflysine (Lys) residue at position 65,[11] and recruits interferon regulatory factor 2 binding protein 1 (IRF2BP1), which acts as anE3 ligase.[23] 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[20] and doublecortin like protein kinase.[24] Polyubiquitination of JDP2 protein is induced by IRF2BP1.[23] JDP2 displays histone-binding and histone-chaperone activity.[25][26] and inhibition of p300/CBP induced histone acetylation (INHAT).[25][26] JDP2 recruits histone deacetylasesHDAC1 andHDAC2,[27][28]HDAC6[27] andHDAC3.[29] JDP2 has INHAT activity[15] and inhibitshistone methylation in vitro.[30]
JDP2 functions as a transcriptionactivator orrepressor depending on the leucine zipper protein member it is associated with. JDP2 forms a homodimer or heterodimer withc-Jun,JUNB,JUND,Fra2,ATF2.[5][8][27] and acts as a general repressor. On the other hand, JDP2 form a stable heterodimer withCHOP10 to enhance TRE- but not CRE-dependent transcription.[34][35] In addition, JDP2 has been shown to directly associate with theprogesterone receptor (PR) and functionally acts as acoactivator of progesterone-dependent PR-mediated gene transcription.[36][37][38] Other proteins such as interferon regulatory factor-2-binding protein-1 (IRF2BP1).[23] CCAAT/enhancer-binding protein gamma (C/EBPγ),[39]HDAC3 andHDAC6[27][29] have also been demonstrated to associate with JDP2.
JDP2 plays a role in cell differentiation in several systems.Ectopic expression of JDP2 inhibits theretinoic acid-induced differentiation of F9 cells[29] and adipocyte differentiation.[40] By contrast, JDP2 induces terminal muscle cell differentiation in C2 myoblasts and reduces the tumorigenicity ofrhabdomyosarcoma cells and restored their ability to differentiate into myotubes.[41] It is also reported that JDP2 plays an important role in the RANK-mediated osteoclast differentiation.[42] Further, JDP2 is involved in neutrophil differentiation[31] and transcription factor Tbx3-mediated osteoclastogenesis[43] for host defense and bone homeostasis.[31] Methylome mapping suggests that JDP2 plays a role in cell progenitor differentiation ofmegakaryocytes.[44]
JDP2 inducescell cycle arrest throughcyclin D,[41] p53, and cyclin A[16] transcription, by increasing JUNB, JUND, and Fra2, and by decreasing c-JUN through the loss of p27kip1.[45] JDP2 downregulatesp53 transcription, which promotes leukemogenesis.[46] Mouse p53 protein negatively regulates the JDP2 promoter in F9 cells[47] as part of the JDP2˗p53 autoregulatory circuit. By contrast, JDP2-knockout mice exhibit in downregulation of p53 and p21 proteins.[16]
JDP2 appears to be involved in the inhibition ofapoptosis. Depletion of JDP2 induces cell death similar to apoptosis.[48] 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.[49] Heart-specific JDP2 overexpression protects cardiomyocytes against hypertrophic growth and TGFβ–induced apoptosis.[50] In other settings, JDP2 has been shown to play an important role in the regulation of cellularsenescence. JDP2-deficient mouse embryonic fibroblasts are resistant to replicative senescence by recruitingpolycomb-repressive complexes (PRC1 andPRC2) to the promoters at thep16Ink4a locus.[25][30]
The increased accumulation of intracellularreactive oxygen species (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.[17][51][52] Furthermore, JDP2 binds directly to the antioxidant responsive element (ARE) core sequence, associates withNrf2 andMafK (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 asHO1 andNQO1.[52] Therefore, JDP2 functions as an integral component of the Nrf2–MafK complex to modulate antioxidant and detoxification programs.
JDP2, which has been shown to regulateWnt signaling pathway and prevent ROS production,[16][17] may play roles in cell reprogramming. Indeed, a study demonstrated that DAOYmedulloblastoma cells can be reprogrammed successfully by JDP2 and the defined factorOCT4 to becomeinduced pluripotent stem cells (iPSC)-like cells. This iPSC-like cells expressed stem cell-like characteristics includingalkaline phosphatase activity and some stem cell markers, includingSSEA3,SSEA4 and Tra-1-60.[17] Later, another study also showed that JDP2 can substitute Oct4 to generate iPSCs withKlf4,Sox2 andMyc (KSM) or KS[clarification needed] from somatic cells.[53] Moreover, they showed that JDP2 anchors five non-Yamanaka factors (ID1,JHDM1B,LRH1,SALL4, andGLIS1) to reprogram mouse embryonic fibroblasts into iPSCs.
JDP2 may act as a double-edge sword intumorigenesis. It is reported that JDP2 inhibits Ras-dependent cell transformation inNIH3T3 cells and tumor development in xenografts transplanted intoSCID mice.[45] Constitutive expression of JDP2 inrhabdomyosarcoma cells reduced their tumorigenic characteristics.[41] On the other hand, JDP2 induces partial oncogenic transformation of chicken embryonic fibroblasts.[9] Studies using high throughput viral insertional mutagenesis analysis also revealed that JDP2 functions as an oncogene.[6][12][13][46][54][55] 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.[56]
JDP2 shows the gene amplification ofhead and neck squamous-cell carcinoma.[57] 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 abiomarker to predict the prognosis of patients with pancreatic cancer.[58] In addition, JDP2 overexpression reverses theepithelial-to-mesenchymal transition (EMT) induced by co-treatment withTGF-β1 andEGF in human pancreaticBxPC-3 cells, suggesting that JDP2 may be a molecular target for pancreatic carcinoma intervention.[59] Furthermore, it has been shown that the expression level of JDP2 gene upon acutemyocardial infarction (AMI) is highly specific and a sensitive biomarker for predicting heart failure.[60] In T cell acute lymphoblastic leukaemia, JDP2 regulates pro-survival signalling through direct transcriptional regulation of MCL1 and leads to steroid resistance in vivo.[61]
JDP2 is involved in the modulation of gene expression. For example, JDP2 regulatesMyoD gene expression with c-Jun[41] and gene forgalectin-7.[62] JDP2 functionally associated with HDAC3 and acts as a repressor to inhibit the amino acid regulation ofCHOP transcription.[34] JDP2 and ATF3 are involved in recruiting HDACs to theATF3 promoter region resulting in transcriptional repression of ATF3.[27] JDP2 inhibits the promoter of the Epstein–Barr virus (EBV) immediate early geneBZLF1 for the regulation of the latent-lytic switch inEBV infection.[63]
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