View source for Jun dimerization protein

{{Infobox_gene}}
'''Jun dimerization protein 2''' (JUNDM2) is a [[protein]] that in humans is encoded by the ''JDP2'' [[gene]].<ref name="Aronheim_1997">{{cite journal | vauthors = Aronheim A, Zandi E, Hennemann H, Elledge SJ, Karin M | title = Isolation of an AP-1 repressor by a novel method for detecting protein-protein interactions | journal = Molecular and Cellular Biology | volume = 17 | issue = 6 | pages = 3094–102 | date = Jun 1997 | pmid = 9154808 | pmc = 232162 | doi =  10.1128/mcb.17.6.3094}}</ref><ref name="pmid17545590">{{cite journal | vauthors = Stewart M, Mackay N, Hanlon L, Blyth K, Scobie L, Cameron E, Neil JC | title = Insertional mutagenesis reveals progression genes and checkpoints in MYC/Runx2 lymphomas | journal = Cancer Research | volume = 67 | issue = 11 | pages = 5126–33 | date = Jun 2007 | pmid = 17545590 | pmc = 2562448 | doi = 10.1158/0008-5472.CAN-07-0433 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: JDP2 jun dimerization protein 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=122953 }}</ref> The Jun dimerization protein is a member of the [[AP-1 (transcription factor)|AP-1]] family of  [[transcription factor]]s.<ref name="Aronheim_1997"/>

JDP 2 was found by a Sos-recruitment system,{{clarify|date=January 2016}} to dimerize with [[c-Jun]] to repress AP-1-mediated activation.<ref name="Aronheim_1997"/> It was later identified by the [[two-hybrid screening|yeast-two hybrid]] system to bind to [[activating transcription factor 2]] (ATF2) to repress ATF-mediated transcriptional activation.<ref name = "Jin_2001">{{cite journal | vauthors = Jin C, Ugai H, Song J, Murata T, Nili F, Sun K, Horikoshi M, Yokoyama KK | title = Identification of mouse Jun dimerization protein 2 as a novel repressor of ATF-2 | journal = FEBS Letters | volume = 489 | issue = 1 | pages = 34–41 | date = Jan 2001 | pmid = 11231009 | doi=10.1016/s0014-5793(00)02387-5}}</ref> JDP2 regulates [[12-O-tetradecanoylphorbol-13-acetate]] (TPA) [[response element]] (TRE)- and [[cyclic adenosine monophosphate|cAMP]]-responsive element (CRE)-dependent transcription.<ref name="Blazek_2003">{{cite journal | vauthors = Blazek E, Wasmer S, Kruse U, Aronheim A, Aoki M, Vogt PK | title = Partial oncogenic transformation of chicken embryo fibroblasts by Jun dimerization protein 2, a negative regulator of TRE- and CRE-dependent transcription | journal = Oncogene | volume = 22 | issue = 14 | pages = 2151–9 | date = Apr 2003 | pmid = 12687017 | doi = 10.1038/sj.onc.1206312 }}</ref>

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),<ref>{{GeneCard|JDP2}}</ref><ref name = "UniProt_Q8WYK2">{{UniProt Full|Q8WYK2}}</ref> which is located at about 250 kbp in the Fos-JDP2-BATF locus.<ref name="Rasmussen_2005">{{cite journal | vauthors = Rasmussen MH, Sørensen AB, Morris DW, Dutra JC, Engelhard EK, Wang CL, Schmidt J, Pedersen FS | title = Tumor model-specific proviral insertional mutagenesis of the Fos/Jdp2/Batf locus | journal = Virology | volume = 337 | issue = 2 | pages = 353–64 | date = Jul 2005 | pmid = 15913695 | doi = 10.1016/j.virol.2005.04.027 }}</ref> [[Alternative splicing]] of JDP2 generates at least two [[protein isoform|isoforms]].<ref name="Rasmussen_2005"/><ref name="Rasmussen_2009">{{cite journal | vauthors = Rasmussen MH, Wang B, Wabl M, Nielsen AL, Pedersen FS | title = Activation of alternative Jdp2 promoters and functional protein isoforms in T-cell lymphomas by retroviral insertion mutagenesis | journal = Nucleic Acids Research | volume = 37 | issue = 14 | pages = 4657–71 | date = Aug 2009 | pmid = 19502497 | doi = 10.1093/nar/gkp469 | pmc=2724284}}</ref> The protein JDP2 has 163 amino acids, belongs to the family of [[bZIP domain|basic leucine zipper]] (bZIP), and shows high homology with the [[ATF3]] bZIP domain.<ref name="Aronheim_1997"/><ref>{{cite journal | vauthors = Weidenfeld-Baranboim K, Hasin T, Darlyuk I, Heinrich R, Elhanani O, Pan J, Yokoyama KK, Aronheim A | title = The ubiquitously expressed bZIP inhibitor, JDP2, suppresses the transcription of its homologue immediate early gene counterpart, ATF3 | journal = Nucleic Acids Research | volume = 37 | issue = 7 | pages = 2194–203 | date = Apr 2009 | pmid = 19233874 | doi = 10.1093/nar/gkp083 | pmc=2673429}}</ref> The bZIP domain includes the amino acids from position 72 to 135, the basic motif from position 74 to 96, and the [[leucine zipper]] from 100 to 128. The molecular weight of the canonical JDP2 is 18,704 Da. The [[histone]]-binding region is located from position 35 to 72 and the inhibition of the [[histone acetyltransferase]] (INHAT) region is from position 35 to 135,<ref name="Jin_2006">{{cite journal | vauthors = Jin C, Kato K, Chimura T, Yamasaki T, Nakade K, Murata T, Li H, Pan J, Zhao M, Sun K, Chiu R, Ito T, Nagata K, Horikoshi M, Yokoyama KK | title = Regulation of histone acetylation and nucleosome assembly by transcription factor JDP2 | journal = Nature Structural & Molecular Biology | volume = 13 | issue = 4 | pages = 331–8 | date = Apr 2006 | pmid = 16518400 | doi = 10.1038/nsmb1063 }}</ref> which is located before the DNA-binding domain.

JDP2 is expressed ubiquitously but is detected mainly in the [[cerebellum]], brain, lung, and testis.<ref name="Pan_2010">{{cite journal | vauthors = Pan J, Nakade K, Huang YC, Zhu ZW, Masuzaki S, Hasegawa H, Murata T, Yoshiki A, Yamaguchi N, Lee CH, Yang WC, Tsai EM, Obata Y, Yokoyama KK | title = Suppression of cell-cycle progression by Jun dimerization protein-2 (JDP2) involves downregulation of cyclin-A2 | journal = Oncogene | volume = 29 | issue = 47 | pages = 6245–56 | date = Nov 2010 | pmid = 20802531 | doi = 10.1038/onc.2010.355 | pmc=3007677}}</ref><ref name="Chiou_2013">{{cite journal | vauthors = Chiou SS, Wang SS, Wu DC, Lin YC, Kao LP, Kuo KK, Wu CC, Chai CY, Lin CL, Lee CY, Liao YM, Wuputra K, Yang YH, Wang SW, Ku CC, Nakamura Y, Saito S, Hasegawa H, Yamaguchi N, Miyoshi H, Lin CS, Eckner R, Yokoyama KK | title = Control of Oxidative Stress and Generation of Induced Pluripotent Stem Cell-like Cells by Jun Dimerization Protein 2 | journal = Cancers | volume = 5 | issue = 3 | pages = 959–84 | date = 26 July 2013 | pmid = 24202329 | doi = 10.3390/cancers5030959 | pmc=3795374}}</ref> A JDP2 [[single nucleotide polymorphism]] (SNP) was detected in Japanese, Korean, and Dutch cohorts, and is associated with an increased risk of [[intracranial aneurysm]]s.<ref>{{cite journal | vauthors = Krischek B, Tajima A, Akagawa H, Narita A, Ruigrok Y, Rinkel G, Wijmenga C, Feigl GC, Kim CJ, Hori T, Tatagiba M, Kasuya H, Inoue I | title = Association of the Jun dimerization protein 2 gene with intracranial aneurysms in Japanese and Korean cohorts as compared to a Dutch cohort | journal = Neuroscience | volume = 169 | issue = 1 | pages = 339–43 | date = Aug 2010 | pmid = 20452405 | doi = 10.1016/j.neuroscience.2010.05.002 }}</ref>

== Posttranscriptional and post translational modifications ==

[[Phosphorylation]] of the [[threonine]] (Thr) residue at position 148 is mediated by c-Jun N-terminal kinase ([[MAPK8]]; [[JNK1]]) and [[p38 mitogen-activated protein kinases|p38 MAPK]].<ref>{{cite journal | vauthors = Katz S, Heinrich R, Aronheim A | title = The AP-1 repressor, JDP2, is a bona fide substrate for the c-Jun N-terminal kinase | journal = FEBS Letters | volume = 506 | issue = 3 | pages = 196–200 | date = Oct 2001 | pmid = 11602244 | doi=10.1016/s0014-5793(01)02907-6}}</ref><ref name="Katz_2002">{{cite journal | vauthors = Katz S, Aronheim A | title = Differential targeting of the stress mitogen-activated protein kinases to the c-Jun dimerization protein 2 | journal = The Biochemical Journal | volume = 368 | issue = Pt 3 | pages = 939–45 | date = Dec 2002 | pmid = 12225289 | doi = 10.1042/BJ20021127 | pmc=1223036}}</ref> Phosphorylated ATF2 inhibits the formation with JDP2 in vitro<ref name="pmid18307971">{{cite journal | vauthors = Murata T, Shinozuka Y, Obata Y, Yokoyama KK | title = Phosphorylation of two eukaryotic transcription factors, Jun dimerization protein 2 and activation transcription factor 2, in Escherichia coli by Jun N-terminal kinase 1 | journal = Analytical Biochemistry | volume = 376 | issue = 1 | pages = 115–21 | date = May 2008 | pmid = 18307971 | doi = 10.1016/j.ab.2008.01.038 }}</ref> while phosphorylated JDP2 undergoes proteosomal degradation.<ref name = "Weidenfeld-Baranboim_2011">{{cite journal | vauthors = Weidenfeld-Baranboim K, Koren L, Aronheim A | title = Phosphorylation of JDP2 on threonine-148 by the c-Jun N-terminal kinase targets it for proteosomal degradation | journal = The Biochemical Journal | volume = 436 | issue = 3 | pages = 661–9 | date = Jun 2011 | pmid = 21463260 | doi = 10.1042/BJ20101031 }}</ref> It contains putative [[SUMO protein|SUMO]] modification of [[lysine]] (Lys) residue at position 65,<ref name = "UniProt_Q8WYK2"/> and recruits interferon regulatory factor 2 binding protein 1 ([[IRF2BP1]]), which acts as an [[ubiquitin ligase|E3 ligase]].<ref name="Kimura_2008">{{cite journal | vauthors = Kimura M | title = IRF2-binding protein-1 is a JDP2 ubiquitin ligase and an inhibitor of ATF2-dependent transcription | journal = FEBS Letters | volume = 582 | issue = 19 | pages = 2833–7 | date = Aug 2008 | pmid = 18671972 | doi = 10.1016/j.febslet.2008.07.033 }}</ref> 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<ref name="Katz_2002"/> and doublecortin like protein kinase.<ref name = "Nagamine_2014">{{cite journal | vauthors = Nagamine T, Nomada S, Onouchi T, Kameshita I, Sueyoshi N | title = Nuclear translocation of doublecortin-like protein kinase and phosphorylation of a transcription factor JDP2 | journal = Biochemical and Biophysical Research Communications | volume = 446 | issue = 1 | pages = 73–8 | date = Mar 2014 | pmid = 24582561 | doi = 10.1016/j.bbrc.2014.02.075 }}</ref> Polyubiquitination of JDP2 protein is induced by IRF2BP1.<ref name="Kimura_2008"/> JDP2 displays histone-binding and histone-chaperone activity.<ref name="Huang_2010">{{cite journal | vauthors = Huang YC, Saito S, Yokoyama KK | title = Histone chaperone Jun dimerization protein 2 (JDP2): role in cellular senescence and aging | journal = The Kaohsiung Journal of Medical Sciences | volume = 26 | issue = 10 | pages = 515–31 | date = Oct 2010 | pmid = 20950777 | doi = 10.1016/S1607-551X(10)70081-4 }}</ref><ref name="Pan_2003">{{cite journal | vauthors = Pan J, Jin C, Murata T, Yokoyama KK | title = Sequence specific transcription factor, JDP2 interacts with histone and inhibits p300-mediated histone acetylation | journal = Nucleic Acids Research. Supplement | issue = 3 | pages = 305–6 | date = 2003 | pmid = 14510502 }}</ref> and inhibition of p300/CBP induced histone acetylation (INHAT).<ref name="Huang_2010"/><ref name="Pan_2003"/> JDP2 recruits histone deacetylases [[HDAC1]] and [[HDAC2]],<ref name="Darlyuk-Saadon_2012">{{cite journal | vauthors = Darlyuk-Saadon I, Weidenfeld-Baranboim K, Yokoyama KK, Hai T, Aronheim A | title = The bZIP repressor proteins, c-Jun dimerization protein 2 and activating transcription factor 3, recruit multiple HDAC members to the ATF3 promoter | journal = Biochimica et Biophysica Acta | volume = 1819 | issue = 11–12 | pages = 1142–53 | date = 2012 | pmid = 22989952 | doi = 10.1016/j.bbagrm.2012.09.005 | pmc=3551276}}</ref><ref>{{cite journal | vauthors = Heideman MR, Wilting RH, Yanover E, Velds A, de Jong J, Kerkhoven RM, Jacobs H, Wessels LF, Dannenberg JH | title = Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function | journal = Blood | volume = 121 | issue = 11 | pages = 2038–50 | date = Mar 2013 | pmid = 23327920 | doi = 10.1182/blood-2012-08-450916 | pmc=3596963}}</ref> [[HDAC6]]<ref name="Darlyuk-Saadon_2012" /> and [[HDAC3]].<ref name="Jin_2002b">{{cite journal | vauthors = Jin C, Li H, Murata T, Sun K, Horikoshi M, Chiu R, Yokoyama KK | title = JDP2, a repressor of AP-1, recruits a histone deacetylase 3 complex to inhibit the retinoic acid-induced differentiation of F9 cells | journal = Molecular and Cellular Biology | volume = 22 | issue = 13 | pages = 4815–26 | date = Jul 2002 | pmid = 12052888 | doi=10.1128/mcb.22.13.4815-4826.2002 | pmc=133911}}</ref> JDP2 has INHAT activity<ref name="Jin_2006"/> and inhibits [[histone methylation]] in vitro.<ref name="Nakade_2009">{{cite journal | vauthors = Nakade K, Pan J, Yamasaki T, Murata T, Wasylyk B, Yokoyama KK | title = JDP2 (Jun Dimerization Protein 2)-deficient mouse embryonic fibroblasts are resistant to replicative senescence | journal = The Journal of Biological Chemistry | volume = 284 | issue = 16 | pages = 10808–17 | date = Apr 2009 | pmid = 19233846 | doi = 10.1074/jbc.M808333200 | pmc=2667768}}</ref>

== Function ==

=== Phenotypes of gene knockout and transgenic mice ===

Gene [[knockout mice]] have a shorter tail, are smaller, have low [[neutrophil]] count.<ref name="Pan_2010"/><ref name="Maruyama_2012">{{cite journal | vauthors = Maruyama K, Fukasaka M, Vandenbon A, Saitoh T, Kawasaki T, Kondo T, Yokoyama KK, Kidoya H, Takakura N, Standley D, Takeuchi O, Akira S | title = The transcription factor Jdp2 controls bone homeostasis and antibacterial immunity by regulating osteoclast and neutrophil differentiation | journal = Immunity | volume = 37 | issue = 6 | pages = 1024–36 | date = Dec 2012 | pmid = 23200825 | doi = 10.1016/j.immuni.2012.08.022 }}</ref> and cell proliferation, and commit to cell cycle arrest because of AP-1 repression.<ref name="Pan_2010"/> TransgenicJDP2 mice display atrial dilation<ref>{{cite journal | vauthors = Kehat I, Heinrich R, Ben-Izhak O, Miyazaki H, Gutkind JS, Aronheim A | title = Inhibition of basic leucine zipper transcription is a major mediator of atrial dilatation | journal = Cardiovascular Research | volume = 70 | issue = 3 | pages = 543–54 | date = Jun 2006 | pmid = 16631626 | doi = 10.1016/j.cardiores.2006.02.018 }}</ref> and [[ventricular hypertrophy|myocardial hypertrophy]].<ref name = "Kehat_2006">{{cite journal | vauthors = Kehat I, Hasin T, Aronheim A | title = The role of basic leucine zipper protein-mediated transcription in physiological and pathological myocardial hypertrophy | journal = Annals of the New York Academy of Sciences | volume = 1080 | pages = 97–109 | date = Oct 2006 | pmid = 17132778 | doi = 10.1196/annals.1380.009 }}</ref>

=== Dimer formation and interacting molecules ===

JDP2 functions as a transcription [[activator (genetics)|activator]] or [[repressor]] depending on the leucine zipper protein member it is associated with. JDP2 forms a homodimer or heterodimer with [[c-Jun]], [[JUNB]], [[JUND]], [[FOSL2|Fra2]], [[ATF2]].<ref name="Aronheim_1997"/><ref name = "Jin_2001"/><ref name="Darlyuk-Saadon_2012"/> and acts as a general repressor. On the other hand, JDP2 form a stable heterodimer with [[DNA damage-inducible transcript 3|CHOP10]] to enhance TRE- but not CRE-dependent transcription.<ref name="Chérasse_2008">{{cite journal | vauthors = Chérasse Y, Chaveroux C, Jousse C, Maurin AC, Carraro V, Parry L, Fafournoux P, Bruhat A | title = Role of the repressor JDP2 in the amino acid-regulated transcription of CHOP | journal = FEBS Letters | volume = 582 | issue = 10 | pages = 1537–41 | date = Apr 2008 | pmid = 18396163 | doi = 10.1016/j.febslet.2008.03.050 }}</ref><ref>{{cite journal | vauthors = Weidenfeld-Baranboim K, Bitton-Worms K, Aronheim A | title = TRE-dependent transcription activation by JDP2-CHOP10 association | journal = Nucleic Acids Research | volume = 36 | issue = 11 | pages = 3608–19 | date = Jun 2008 | pmid = 18463134 | doi = 10.1093/nar/gkn268 | pmc=2441799}}</ref> In addition, JDP2 has been shown to directly associate with the [[progesterone receptor]] (PR) and functionally acts as a [[coactivator (genetics)|coactivator]] of progesterone-dependent PR-mediated gene transcription.<ref>{{cite journal | vauthors = Hill KK, Roemer SC, Jones DN, Churchill ME, Edwards DP | title = A progesterone receptor co-activator (JDP2) mediates activity through interaction with residues in the carboxyl-terminal extension of the DNA binding domain | journal = The Journal of Biological Chemistry | volume = 284 | issue = 36 | pages = 24415–24 | date = Sep 2009 | pmid = 19553667 | doi = 10.1074/jbc.M109.003244 | pmc=2782034}}</ref><ref>{{cite journal | vauthors = Wardell SE, Boonyaratanakornkit V, Adelman JS, Aronheim A, Edwards DP | title = Jun dimerization protein 2 functions as a progesterone receptor N-terminal domain coactivator | journal = Molecular and Cellular Biology | volume = 22 | issue = 15 | pages = 5451–66 | date = Aug 2002 | pmid = 12101239 | doi=10.1128/mcb.22.15.5451-5466.2002 | pmc=133955| url = https://works.bepress.com/james_adelman/8/download/ }}</ref><ref>{{cite journal | vauthors = Edwards DP, Wardell SE, Boonyaratanakornkit V | title = Progesterone receptor interacting coregulatory proteins and cross talk with cell signaling pathways | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 83 | issue = 1–5 | pages = 173–86 | date = Dec 2002 | pmid = 12650714 | doi=10.1016/s0960-0760(02)00265-0}}</ref> Other proteins such as interferon regulatory factor-2-binding protein-1 ([[IRF2BP1]]).<ref name="Kimura_2008"/> CCAAT/enhancer-binding protein gamma (C/EBPγ),<ref>{{cite journal | vauthors = Broder YC, Katz S, Aronheim A | title = The ras recruitment system, a novel approach to the study of protein-protein interactions | journal = Current Biology | volume = 8 | issue = 20 | pages = 1121–4 | date = Oct 1998 | pmid = 9778531 | doi=10.1016/s0960-9822(98)70467-1}}</ref> [[HDAC3]] and [[HDAC6]]<ref name="Darlyuk-Saadon_2012"/><ref name="Jin_2002b"/> have also been demonstrated to associate with JDP2.

=== Cell differentiation ===

JDP2 plays a role in cell differentiation in several systems. [[Ectopic expression]] of JDP2 inhibits the [[retinoic acid]]-induced differentiation of F9 cells<ref name="Jin_2002b"/> and adipocyte differentiation.<ref>{{cite journal | vauthors = Nakade K, Pan J, Yoshiki A, Ugai H, Kimura M, Liu B, Li H, Obata Y, Iwama M, Itohara S, Murata T, Yokoyama KK | title = JDP2 suppresses adipocyte differentiation by regulating histone acetylation | journal = Cell Death and Differentiation | volume = 14 | issue = 8 | pages = 1398–405 | date = Aug 2007 | pmid = 17464331 | doi = 10.1038/sj.cdd.4402129 }}</ref> By contrast, JDP2 induces terminal muscle cell differentiation in C2 myoblasts and reduces the tumorigenicity of [[rhabdomyosarcoma]] cells and restored their ability to differentiate into myotubes.<ref name="Ostrovsky_2002">{{cite journal | vauthors = Ostrovsky O, Bengal E, Aronheim A | title = Induction of terminal differentiation by the c-Jun dimerization protein JDP2 in C2 myoblasts and rhabdomyosarcoma cells | journal = The Journal of Biological Chemistry | volume = 277 | issue = 42 | pages = 40043–54 | date = Oct 2002 | pmid = 12171923 | doi = 10.1074/jbc.M205494200 }}</ref> It is also reported that JDP2 plays an important role in the RANK-mediated osteoclast differentiation.<ref name="Kawaida_2003">{{cite journal | vauthors = Kawaida R, Ohtsuka T, Okutsu J, Takahashi T, Kadono Y, Oda H, Hikita A, Nakamura K, Tanaka S, Furukawa H | title = Jun dimerization protein 2 (JDP2), a member of the AP-1 family of transcription factor, mediates osteoclast differentiation induced by RANKL | journal = The Journal of Experimental Medicine | volume = 197 | issue = 8 | pages = 1029–35 | date = Apr 2003 | pmid = 12707301 | doi = 10.1084/jem.20021321 | pmc=2193879}}</ref> Further, JDP2 is involved in neutrophil differentiation<ref name="Maruyama_2012"/> and transcription factor Tbx3-mediated osteoclastogenesis<ref>{{cite journal | vauthors = Yao C, Yao GQ, Sun BH, Zhang C, Tommasini SM, Insogna K | title = The transcription factor T-box 3 regulates colony-stimulating factor 1-dependent Jun dimerization protein 2 expression and plays an important role in osteoclastogenesis | journal = The Journal of Biological Chemistry | volume = 289 | issue = 10 | pages = 6775–90 | date = Mar 2014 | pmid = 24394418 | doi = 10.1074/jbc.M113.499210 | pmc=3945339}}</ref> for host defense and bone homeostasis.<ref name="Maruyama_2012"/> Methylome mapping suggests that JDP2 plays a role in cell progenitor differentiation of [[megakaryocyte]]s.<ref>{{cite journal | vauthors = Ji H, Ehrlich LI, Seita J, Murakami P, Doi A, Lindau P, Lee H, Aryee MJ, Irizarry RA, Kim K, Rossi DJ, Inlay MA, Serwold T, Karsunky H, Ho L, Daley GQ, Weissman IL, Feinberg AP | title = Comprehensive methylome map of lineage commitment from haematopoietic progenitors | journal = Nature | volume = 467 | issue = 7313 | pages = 338–42 | date = Sep 2010 | pmid = 20720541 | doi = 10.1038/nature09367 | pmc=2956609}}</ref>

=== Regulation of cell cycle and p53 signaling ===

JDP2 induces [[cell cycle]] arrest through [[cyclin D]],<ref name="Ostrovsky_2002"/> p53, and cyclin A<ref name="Pan_2010"/> transcription, by increasing JUNB, JUND, and Fra2, and by decreasing c-JUN through the loss of p27kip1.<ref name="Heinrich_2004">{{cite journal | vauthors = Heinrich R, Livne E, Ben-Izhak O, Aronheim A | title = The c-Jun dimerization protein 2 inhibits cell transformation and acts as a tumor suppressor gene | journal = The Journal of Biological Chemistry | volume = 279 | issue = 7 | pages = 5708–15 | date = Feb 2004 | pmid = 14627710 | doi = 10.1074/jbc.M307608200 }}</ref> JDP2 downregulates [[p53]] transcription, which promotes leukemogenesis.<ref name="van_der_Weyden_2013">{{cite journal | vauthors = van der Weyden L, Rust AG, McIntyre RE, Robles-Espinoza CD, del Castillo Velasco-Herrera M, Strogantsev R, Ferguson-Smith AC, McCarthy S, Keane TM, Arends MJ, Adams DJ | title = Jdp2 downregulates Trp53 transcription to promote leukaemogenesis in the context of Trp53 heterozygosity | journal = Oncogene | volume = 32 | issue = 3 | pages = 397–402 | date = Jan 2013 | pmid = 22370638 | doi = 10.1038/onc.2012.56 | pmc=3550594}}</ref> Mouse p53 protein negatively regulates the JDP2 promoter in F9 cells<ref name="Xu_2014">{{cite journal | vauthors = Xu Y, Jin C, Liu Z, Pan J, Li H, Zhang Z, Bi S, Yokoyama KK | title = Cloning and characterization of the mouse JDP2 gene promoter reveal negative regulation by p53 | journal = Biochemical and Biophysical Research Communications | volume = 450 | issue = 4 | pages = 1531–6 | date = Aug 2014 | pmid = 25026555 | doi = 10.1016/j.bbrc.2014.07.034 }}</ref> as part of the JDP2˗p53 autoregulatory circuit. By contrast, JDP2-knockout mice exhibit in downregulation of p53 and p21 proteins.<ref name="Pan_2010"/>

=== Apoptosis and senescence ===

JDP2 appears to be involved in the inhibition of [[apoptosis]]. Depletion of JDP2 induces cell death similar to apoptosis.<ref>{{cite journal | vauthors = Lerdrup M, Holmberg C, Dietrich N, Shaulian E, Herdegen T, Jäättelä M, Kallunki T | title = Depletion of the AP-1 repressor JDP2 induces cell death similar to apoptosis | journal = Biochimica et Biophysica Acta | volume = 1745 | issue = 1 | pages = 29–37 | date = Aug 2005 | pmid = 16026868 | doi = 10.1016/j.bbamcr.2005.06.008 }}</ref> 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.<ref>{{cite journal | vauthors = Piu F, Aronheim A, Katz S, Karin M | title = AP-1 repressor protein JDP-2: inhibition of UV-mediated apoptosis through p53 down-regulation | journal = Molecular and Cellular Biology | volume = 21 | issue = 9 | pages = 3012–24 | date = May 2001 | pmid = 11287607 | doi = 10.1128/MCB.21.9.3012-3024.2001 | pmc=86930}}</ref> Heart-specific JDP2 overexpression protects cardiomyocytes against hypertrophic growth and TGFβ–induced apoptosis.<ref>{{cite journal | vauthors = Hill C, Würfel A, Heger J, Meyering B, Schlüter KD, Weber M, Ferdinandy P, Aronheim A, Schulz R, Euler G | title = Inhibition of AP-1 signaling by JDP2 overexpression protects cardiomyocytes against hypertrophy and apoptosis induction | journal = Cardiovascular Research | volume = 99 | issue = 1 | pages = 121–8 | date = Jul 2013 | pmid = 23612584 | doi = 10.1093/cvr/cvt094 }}</ref> In other settings, JDP2 has been shown to play an important role in the regulation of cellular [[senescence]]. JDP2-deficient mouse embryonic fibroblasts are resistant to replicative senescence by recruiting [[polycomb-group proteins|polycomb]]-repressive complexes (PRC1 and [[PRC2]]) to the promoters at the [[CDKN2A|p16Ink4a]] locus.<ref name="Huang_2010"/><ref name="Nakade_2009"/>

=== Oxidative stress and antioxidative response ===

The increased accumulation of intracellular [[reactive 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.<ref name="Chiou_2013"/><ref>{{cite journal | vauthors = Wang SW, Lee JK, Ku CC, Chiou SS, Steve Lin CL, Ho MF, Wu DC, Yokoyama KK | title = Jun dimerization protein 2 in oxygen restriction; control of senescence | journal = Current Pharmaceutical Design | volume = 17 | issue = 22 | pages = 2278–89 | date = 2011 | pmid = 21736542 | doi=10.2174/138161211797052394}}</ref><ref name="Tanigawa_2013">{{cite journal | vauthors = Tanigawa S, Lee CH, Lin CS, Ku CC, Hasegawa H, Qin S, Kawahara A, Korenori Y, Miyamori K, Noguchi M, Lee LH, Lin YC, Steve Lin CL, Nakamura Y, Jin C, Yamaguchi N, Eckner R, Hou DX, Yokoyama KK | title = Jun dimerization protein 2 is a critical component of the Nrf2/MafK complex regulating the response to ROS homeostasis | journal = Cell Death & Disease | volume = 4 | pages = e921 | date = 14 November 2013 | pmid = 24232097 | doi = 10.1038/cddis.2013.448 | pmc=3847324}}</ref> Furthermore, JDP2 binds directly to the antioxidant responsive element (ARE) core sequence, associates with [[NFE2L2|Nrf2]] and [[MAFK|MafK]] (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 [[HMOX1|HO1]] and [[NQO1]].<ref name="Tanigawa_2013"/> 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]] and prevent ROS production,<ref name="Pan_2010"/><ref name="Chiou_2013"/> may play roles in cell reprogramming. Indeed, a study demonstrated that DAOY [[medulloblastoma]] cells can be reprogrammed successfully by JDP2 and the defined factor [[OCT4]] to become [[induced pluripotent stem cell]]s (iPSC)-like cells. This iPSC-like cells expressed stem cell-like characteristics including [[alkaline phosphatase]] activity and some stem cell markers, including [[Stage specific embryonic antigen 3|SSEA3]], [[Stage specific embryonic antigen 4|SSEA4]] and Tra-1-60.<ref name="Chiou_2013"/> Later, another study also showed that JDP2 can substitute Oct4 to generate iPSCs with [[Klf4]], [[Sox2]] and [[Myc]] (KSM) or KS{{clarify|date=January 2016}} from somatic cells.<ref>{{cite journal | vauthors = Liu J, Han Q, Peng T, Peng M, Wei B, Li D, Wang X, Yu S, Yang J, Cao S, Huang K, Hutchins AP, Liu H, Kuang J, Zhou Z, Chen J, Wu H, Guo L, Chen Y, Chen Y, Li X, Wu H, Liao B, He W, Song H, Yao H, Pan G, Chen J, Pei D | title = The oncogene c-Jun impedes somatic cell reprogramming | journal = Nature Cell Biology | volume = 17 | issue = 7 | pages = 856–67 | date = Jul 2015 | pmid = 26098572 | doi = 10.1038/ncb3193 }}</ref> Moreover, they showed that JDP2 anchors five non-Yamanaka factors ([[ID1]], [[KDM2B|JHDM1B]], [[Liver receptor homolog-1|LRH1]], [[SALL4]], and [[GLIS1]]) to reprogram mouse embryonic fibroblasts into iPSCs.

== Oncogene or tumor suppressor gene ==

JDP2 may act as a double-edge sword in [[tumorigenesis]]. It is reported that JDP2 inhibits Ras-dependent cell transformation in [[3T3 cells|NIH3T3 cells]] and tumor development in xenografts transplanted into [[SCID mice]].<ref name="Heinrich_2004"/> Constitutive expression of JDP2 in [[rhabdomyosarcoma]] cells reduced their tumorigenic characteristics.<ref name="Ostrovsky_2002"/> On the other hand, JDP2 induces partial oncogenic transformation of chicken embryonic fibroblasts.<ref name="Blazek_2003"/> Studies using high throughput viral insertional mutagenesis analysis also revealed that JDP2 functions as an oncogene.<ref name="pmid17545590" /><ref name="Rasmussen_2005"/><ref name="Rasmussen_2009"/><ref name="van_der_Weyden_2013"/><ref>{{cite journal | vauthors = Hwang HC, Martins CP, Bronkhorst Y, Randel E, Berns A, Fero M, Clurman BE | title = Identification of oncogenes collaborating with p27Kip1 loss by insertional mutagenesis and high-throughput insertion site analysis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 17 | pages = 11293–8 | date = Aug 2002 | pmid = 12151601 | doi = 10.1073/pnas.162356099 | pmc=123250}}</ref><ref>{{cite journal | vauthors = Rasmussen MH, Ballarín-González B, Liu J, Lassen LB, Füchtbauer A, Füchtbauer EM, Nielsen AL, Pedersen FS | title = Antisense transcription in gammaretroviruses as a mechanism of insertional activation of host genes | journal = Journal of Virology | volume = 84 | issue = 8 | pages = 3780–8 | date = Apr 2010 | pmid = 20130045 | doi = 10.1128/JVI.02088-09 | pmc=2849499}}</ref> 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.<ref>{{cite journal | vauthors = Bitton-Worms K, Pikarsky E, Aronheim A | title = The AP-1 repressor protein, JDP2, potentiates hepatocellular carcinoma in mice | journal = Molecular Cancer | volume = 9 | pages = 54 | date = 9 March 2010 | pmid = 20214788 | doi = 10.1186/1476-4598-9-54 | pmc=2841123}}</ref>

== Cancer and disease markers ==

JDP2 shows the gene amplification of [[head and neck squamous-cell carcinoma]].<ref>{{cite journal | vauthors = Järvinen AK, Autio R, Kilpinen S, Saarela M, Leivo I, Grénman R, Mäkitie AA, Monni O | title = High-resolution copy number and gene expression microarray analyses of head and neck squamous cell carcinoma cell lines of tongue and larynx | journal = Genes, Chromosomes & Cancer | volume = 47 | issue = 6 | pages = 500–9 | date = Jun 2008 | pmid = 18314910 | doi = 10.1002/gcc.20551 }}</ref> 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]] to predict the prognosis of patients with pancreatic cancer.<ref>{{cite journal | vauthors = Yuanhong X, Feng X, Qingchang L, Jianpeng F, Zhe L, Kejian G | title = Downregulation of AP-1 repressor JDP2 is associated with tumor metastasis and poor prognosis in patients with pancreatic carcinoma | journal = The International Journal of Biological Markers | volume = 25 | issue = 3 | pages = 136–40 | date = 2009 | pmid = 20677166 }}</ref> In addition, JDP2 overexpression reverses the [[epithelial-to-mesenchymal transition]] (EMT) induced by co-treatment with [[TGF-β1]] and [[epidermal growth factor|EGF]] in human pancreatic [[BxPC-3]] cells, suggesting that JDP2 may be a molecular target for pancreatic carcinoma intervention.<ref>{{cite journal | vauthors = Liu Z, Du R, Long J, Dong A, Fan J, Guo K, Xu Y | title = JDP2 inhibits the epithelial-to-mesenchymal transition in pancreatic cancer BxPC3 cells | journal = Tumour Biology | volume = 33 | issue = 5 | pages = 1527–34 | date = Oct 2012 | pmid = 22535371 | doi = 10.1007/s13277-012-0404-5 }}</ref> Furthermore, it has been shown that the expression level of JDP2 gene upon acute [[myocardial infarction]] (AMI) is highly specific and a sensitive biomarker for predicting heart failure.<ref name = "Maciejak_2015">{{cite journal | vauthors = Maciejak A, Kiliszek M, Michalak M, Tulacz D, Opolski G, Matlak K, Dobrzycki S, Segiet A, Gora M, Burzynska B | title = Gene expression profiling reveals potential prognostic biomarkers associated with the progression of heart failure | journal = Genome Medicine | volume = 7 | issue = 1 | pages = 26 | date = 2015 | pmid = 25984239 | doi = 10.1186/s13073-015-0149-z | pmc=4432772}}</ref>

== JDP2 targets and JDP2-regulated genes ==

JDP2 is involved in the modulation of gene expression. For example, JDP2 regulates [[MyoD]] gene expression with c-Jun<ref name="Ostrovsky_2002"/> and gene for [[LGALS7|galectin-7]].<ref>{{cite journal | vauthors = Barkan B, Cox AD, Kloog Y | title = Ras inhibition boosts galectin-7 at the expense of galectin-1 to sensitize cells to apoptosis | journal = Oncotarget | volume = 4 | issue = 2 | pages = 256–68 | date = Feb 2013 | pmid = 23530091 | doi = 10.18632/oncotarget.844 | pmc=3712571}}</ref> JDP2 functionally associated with HDAC3 and acts as a repressor to inhibit the amino acid regulation of [[DNA damage-inducible transcript 3|CHOP]] transcription.<ref name="Chérasse_2008"/> JDP2 and ATF3 are involved in recruiting HDACs to the [[ATF3]] promoter region resulting in transcriptional repression of ATF3.<ref name="Darlyuk-Saadon_2012"/> JDP2 inhibits the promoter of the Epstein–Barr virus (EBV) immediate early gene [[BZLF1]] for the regulation of the latent-lytic switch in [[Epstein–Barr virus|EBV]] infection.<ref>{{cite journal | vauthors = Murata T, Noda C, Saito S, Kawashima D, Sugimoto A, Isomura H, Kanda T, Yokoyama KK, Tsurumi T | title = Involvement of Jun dimerization protein 2 (JDP2) in the maintenance of Epstein-Barr virus latency | journal = The Journal of Biological Chemistry | volume = 286 | issue = 25 | pages = 22007–16 | date = Jun 2011 | pmid = 21525011 | doi = 10.1074/jbc.M110.199836 | pmc=3121345}}</ref>

== Interactions ==

JDP2 (gene) has been shown to [[Protein-protein interaction|interact]] with [[Activating transcription factor 2]].<ref name="pmid18307971"/>

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Lerdrup M, Holmberg C, Dietrich N, Shaulian E, Herdegen T, Jäättelä M, Kallunki T | title = Depletion of the AP-1 repressor JDP2 induces cell death similar to apoptosis | journal = Biochimica et Biophysica Acta | volume = 1745 | issue = 1 | pages = 29–37 | date = Aug 2005 | pmid = 16026868 | doi = 10.1016/j.bbamcr.2005.06.008 }}
{{refend}}

==External links==
* {{MeshName|JDP2 protein}}

{{Oncogenes}}
{{Transcription factors|g1}}

[[Category:Transcription factors]]