Jun dimerization protein: Difference between revisions

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I am an expert on JDP2 and would like to help update this page, but struggling with the formatting and that help would be appreciated.
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The Jun dimerization protein is a member of the [[AP-1 (transcription factor)|AP-1]] family of [[transcription factor]]s.<ref name="Aronheim"/>
The Jun dimerization protein is a member of the [[AP-1 (transcription factor)|AP-1]] family of [[transcription factor]]s.<ref name="Aronheim"/>


Jun dimerization protein 2 (JUNDM2) is a member of the activating protein-1 (AP-1) family of transcription factors, was found by the Sos recruitment system, to dimerize with c-Jun to repress AP-1-mediated activation (1)<ref>{{cite journal|last1=Aronheim|first1=A|last2=Zandi|first2=E|last3=Hennemann|first3=H|last4=Elledge|first4=SJ|last5=Karin|first5=M|title=Isolation of an AP-1 repressor by a novel method for detecting protein-protein interactions.|journal=Molecular and cellular biology|date=June 1997|volume=17|issue=6|pages=3094-102|pmid=9154808}}</ref>. It was later identified by the yeast-two hybrid system to bind to activation transcription factor 2 (ATF2) to repress ATF-mediated transcriptional activation (2)<ref>{{cite journal|last1=Jin|first1=C|last2=Ugai|first2=H|last3=Song|first3=J|last4=Murata|first4=T|last5=Nili|first5=F|last6=Sun|first6=K|last7=Horikoshi|first7=M|last8=Yokoyama|first8=KK|title=Identification of mouse Jun dimerization protein 2 as a novel repressor of ATF-2.|journal=FEBS letters|date=26 January 2001|volume=489|issue=1|pages=34-41|pmid=11231009}}</ref>. JDP2 regulates 12-O-tetradecanoylphorbol-13-acetate (TPA) response element (TRE)- and cAMP-responsive element (CRE)-dependent transcription (3)<ref>{{cite journal|last1=Blazek|first1=E|last2=Wasmer|first2=S|last3=Kruse|first3=U|last4=Aronheim|first4=A|last5=Aoki|first5=M|last6=Vogt|first6=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|date=10 April 2003|volume=22|issue=14|pages=2151-9|pmid=12687017}}</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) (4)<ref>{{cite web|url=http://www.genecards.org.cbi-bin/carddisp.pl?gene=JDP2}}</ref><ref>{{cite web|url=and http://www.uniprot.org/uniprot/Q8WYK2}}</ref>, which is located at about 250 kbp in the Fos-JDP2-BATF locus (5)<ref name=#5>{{cite journal|last1=Rasmussen|first1=MH|last2=Sørensen|first2=AB|last3=Morris|first3=DW|last4=Dutra|first4=JC|last5=Engelhard|first5=EK|last6=Wang|first6=CL|last7=Schmidt|first7=J|last8=Pedersen|first8=FS|title=Tumor model-specific proviral insertional mutagenesis of the Fos/Jdp2/Batf locus.|journal=Virology|date=5 July 2005|volume=337|issue=2|pages=353-64|pmid=15913695}}</ref>. JDP2 is expressed ubiquitously but is detected mainly in the cerebellum, brain, lung, and testis (6, 7)<ref name=#6>{{cite journal|last1=Pan|first1=J|last2=Nakade|first2=K|last3=Huang|first3=YC|last4=Zhu|first4=ZW|last5=Masuzaki|first5=S|last6=Hasegawa|first6=H|last7=Murata|first7=T|last8=Yoshiki|first8=A|last9=Yamaguchi|first9=N|last10=Lee|first10=CH|last11=Yang|first11=WC|last12=Tsai|first12=EM|last13=Obata|first13=Y|last14=Yokoyama|first14=KK|title=Suppression of cell-cycle progression by Jun dimerization protein-2 (JDP2) involves downregulation of cyclin-A2.|journal=Oncogene|date=25 November 2010|volume=29|issue=47|pages=6245-56|pmid=20802531}}</ref><ref name=#7>{{cite journal|last1=Chiou|first1=SS|last2=Wang|first2=SS|last3=Wu|first3=DC|last4=Lin|first4=YC|last5=Kao|first5=LP|last6=Kuo|first6=KK|last7=Wu|first7=CC|last8=Chai|first8=CY|last9=Lin|first9=CL|last10=Lee|first10=CY|last11=Liao|first11=YM|last12=Wuputra|first12=K|last13=Yang|first13=YH|last14=Wang|first14=SW|last15=Ku|first15=CC|last16=Nakamura|first16=Y|last17=Saito|first17=S|last18=Hasegawa|first18=H|last19=Yamaguchi|first19=N|last20=Miyoshi|first20=H|last21=Lin|first21=CS|last22=Eckner|first22=R|last23=Yokoyama|first23=KK|title=Control of Oxidative Stress and Generation of Induced Pluripotent Stem Cell-like Cells by Jun Dimerization Protein 2.|journal=Cancers|date=26 July 2013|volume=5|issue=3|pages=959-84|pmid=24202329}}</ref>. The single nucleotide polymorphism (SNP) was detected in Japanese, Korean, and Dutch cohorts, belongs to the family of intracranial aneurysms (8)<ref>{{cite journal|last1=Krischek|first1=B|last2=Tajima|first2=A|last3=Akagawa|first3=H|last4=Narita|first4=A|last5=Ruigrok|first5=Y|last6=Rinkel|first6=G|last7=Wijmenga|first7=C|last8=Feigl|first8=GC|last9=Kim|first9=CJ|last10=Hori|first10=T|last11=Tatagiba|first11=M|last12=Kasuya|first12=H|last13=Inoue|first13=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|date=11 August 2010|volume=169|issue=1|pages=339-43|pmid=20452405}}</ref>. The alternative splicing of JDP2 generates at least two isoforms (5, 9)<ref name=#5>{{cite journal|last1=Rasmussen|first1=MH|last2=Sørensen|first2=AB|last3=Morris|first3=DW|last4=Dutra|first4=JC|last5=Engelhard|first5=EK|last6=Wang|first6=CL|last7=Schmidt|first7=J|last8=Pedersen|first8=FS|title=Tumor model-specific proviral insertional mutagenesis of the Fos/Jdp2/Batf locus.|journal=Virology|date=5 July 2005|volume=337|issue=2|pages=353-64|pmid=15913695}}</ref><ref>{{cite journal|last1=Rasmussen|first1=MH|last2=Wang|first2=B|last3=Wabl|first3=M|last4=Nielsen|first4=AL|last5=Pedersen|first5=FS|title=Activation of alternative Jdp2 promoters and functional protein isoforms in T-cell lymphomas by retroviral insertion mutagenesis.|journal=Nucleic Acids Research|date=August 2009|volume=37|issue=14|pages=4657-71|pmid=19502497}}</ref>. The protein JDP2 has 163 amino acids, belongs to the family of basic leucine zippers (bZIP), and shows great homology with the ATF-3 bZIP domain (1, 10)<ref name=#1>{{cite journal|last1=Aronheim|first1=A|last2=Zandi|first2=E|last3=Hennemann|first3=H|last4=Elledge|first4=SJ|last5=Karin|first5=M|title=Isolation of an AP-1 repressor by a novel method for detecting protein-protein interactions.|journal=Molecular and Cellular Biology|date=June 1997|volume=17|issue=6|pages=3094-102|pmid=9154808}}</ref><ref>{{cite journal|last1=Weidenfeld-Baranboim|first1=K|last2=Hasin|first2=T|last3=Darlyuk|first3=I|last4=Heinrich|first4=R|last5=Elhanani|first5=O|last6=Pan|first6=J|last7=Yokoyama|first7=KK|last8=Aronheim|first8=A|title=The ubiquitously expressed bZIP inhibitor, JDP2, suppresses the transcription of its homologue immediate early gene counterpart, ATF3.|journal=Nucleic acids research|date=April 2009|volume=37|issue=7|pages=2194-203|pmid=19233874}}</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 (11)<ref name=#11>{{cite journal|last1=Jin|first1=C|last2=Kato|first2=K|last3=Chimura|first3=T|last4=Yamasaki|first4=T|last5=Nakade|first5=K|last6=Murata|first6=T|last7=Li|first7=H|last8=Pan|first8=J|last9=Zhao|first9=M|last10=Sun|first10=K|last11=Chiu|first11=R|last12=Ito|first12=T|last13=Nagata|first13=K|last14=Horikoshi|first14=M|last15=Yokoyama|first15=KK|title=Regulation of histone acetylation and nucleosome assembly by transcription factor JDP2.|journal=Nature Structural & Molecular Biology|date=April 2006|volume=13|issue=4|pages=331-8|pmid=16518400}}</ref>, which is located before the DNA-binding domain.

==Posttranscriptional and posttranslational modifications==
Phosphorylation of the threonine (Thr) residue at position 148 is mediated by c-Jun N-terminal kinase (MAPK8; JNK1) and p38 MAPK (12, 13)<ref>{{cite journal|pmid=11602244}}</ref><ref name=#13>{{cite journal|last1=Katz|first1=S|last2=Aronheim|first2=A|title=Differential targeting of the stress mitogen-activated protein kinases to the c-Jun dimerization protein 2.|journal=The Biochemical Journal|date=15 December 2002|volume=368|issue=Pt 3|pages=939-45|pmid=12225289}}</ref>. Phosphorylated ATF2 inhibits the formation with JDP2 in vitro (14)<ref>{{cite journal|last1=Murata|first1=T|last2=Shinozuka|first2=Y|last3=Obata|first3=Y|last4=Yokoyama|first4=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|date=1 May 2008|volume=376|issue=1|pages=115-21|pmid=18307971}}</ref> while phosphorylated JDP2 undergoes proteosomal degradation (15)<ref>{{cite journal|last1=Weidenfeld-Baranboim|first1=K|last2=Koren|first2=L|last3=Aronheim|first3=A|title=Phosphorylation of JDP2 on threonine-148 by the c-Jun N-terminal kinase targets it for proteosomal degradation.|journal=The Biochemical Journal|date=15 June 2011|volume=436|issue=3|pages=661-9|pmid=21463260}}</ref>. It contains putative SUMO modification of lysine (Lys) residue at position 65 (4; http://www.uniprot.org/uniprot/Q8WYK2), and recruits interferon regulatory factor 2 binding protein 1 (IRF2BP1), which acts as an E3 ligase (16)<ref name=#16>{{cite journal|last1=Kimura|first1=M|title=IRF2-binding protein-1 is a JDP2 ubiquitin ligase and an inhibitor of ATF2-dependent transcription.|journal=FEBS Letters|date=20 August 2008|volume=582|issue=19|pages=2833-7|pmid=18671972}}</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 (13)<ref name=#13 /> and doublecortin like protein kinase (17)<ref>{{cite journal|pmid=24582561}}</ref>. Polyubiquitination of JDP2 protein is induced by IRF2BP1 (16)<ref name=#16 />. JDP2 displays histone-binding and histone-chaperone activity (18, 19)<ref name=#18>{{cite journal|last1=Huang|first1=YC|last2=Saito|first2=S|last3=Yokoyama|first3=KK|title=Histone chaperone Jun dimerization protein 2 (JDP2): role in cellular senescence and aging.|journal=The Kaohsiung journal of medical sciences|date=October 2010|volume=26|issue=10|pages=515-31|pmid=20950777}}</ref><ref name=#19>{{cite journal|last1=Pan|first1=J|last2=Jin|first2=C|last3=Murata|first3=T|last4=Yokoyama|first4=KK|title=Sequence specific transcription factor, JDP2 interacts with histone and inhibits p300-mediated histone acetylation.|journal=Nucleic Acids Research. Supplement (2001)|date=2003|issue=3|pages=305-6|pmid=14510502}}</ref> and inhibition of p300/CBP induced histone acetylation (INHAT) (18, 19)<ref name=#18>{{cite journal|last1=Huang|first1=YC|last2=Saito|first2=S|last3=Yokoyama|first3=KK|title=Histone chaperone Jun dimerization protein 2 (JDP2): role in cellular senescence and aging.|journal=The Kaohsiung Journal of Medical Sciences|date=October 2010|volume=26|issue=10|pages=515-31|pmid=20950777}}</ref><ref name=#19>{{cite journal|last1=Pan|first1=J|last2=Jin|first2=C|last3=Murata|first3=T|last4=Yokoyama|first4=KK|title=Sequence specific transcription factor, JDP2 interacts with histone and inhibits p300-mediated histone acetylation.|journal=Nucleic Acids Research. Supplement (2001)|date=2003|issue=3|pages=305-6|pmid=14510502}}</ref>. JDP2 recruits histone deacetylase (HDAC) 1, HDAC2 (20, 21)<ref name=#20>{{cite journal|last1=Darlyuk-Saadon|first1=I|last2=Weidenfeld-Baranboim|first2=K|last3=Yokoyama|first3=KK|last4=Hai|first4=T|last5=Aronheim|first5=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|date=2012|volume=1819|issue=11-12|pages=1142-53|pmid=22989952}}</ref><ref>{{cite journal|last1=Heideman|first1=MR|last2=Wilting|first2=RH|last3=Yanover|first3=E|last4=Velds|first4=A|last5=de Jong|first5=J|last6=Kerkhoven|first6=RM|last7=Jacobs|first7=H|last8=Wessels|first8=LF|last9=Dannenberg|first9=JH|title=Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function.|journal=Blood|date=14 March 2013|volume=121|issue=11|pages=2038-50|pmid=23327920}}</ref>, HDAC6 (20)<ref name=#20>{{cite journal|last1=Darlyuk-Saadon|first1=I|last2=Weidenfeld-Baranboim|first2=K|last3=Yokoyama|first3=KK|last4=Hai|first4=T|last5=Aronheim|first5=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|date=2011|volume=1819|issue=11-12|pages=1142-53|pmid=22989952}}</ref> and HDAC3 (22)<ref name="#22 MCB2002">{{cite journal|last1=Jin|first1=C|last2=Li|first2=H|last3=Murata|first3=T|last4=Sun|first4=K|last5=Horikoshi|first5=M|last6=Chiu|first6=R|last7=Yokoyama|first7=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|date=July 2002|volume=22|issue=13|pages=4815-26|pmid=12052888}}</ref>. JDP2 has INHAT activity (11)<ref name=#11 /> and inhibits histone methylation in vitro (23)<ref name="#23 JBC">{{cite journal|last1=Nakade|first1=K|last2=Pan|first2=J|last3=Yamasaki|first3=T|last4=Murata|first4=T|last5=Wasylyk|first5=B|last6=Yokoyama|first6=KK|title=JDP2 (Jun Dimerization Protein 2)-deficient mouse embryonic fibroblasts are resistant to replicative senescence.|journal=The Journal of Biological Chemistry|date=17 April 2009|volume=284|issue=16|pages=10808-17|pmid=19233846}}</ref>.

==Function==
===Phenotypes of gene knockout and transgenic mice===
Gene knockout mice have a shorter tail, are smaller, have low neutrophil count <ref name=#6 /><ref name="#24 Immunity">{{cite journal|last1=Maruyama|first1=K|last2=Fukasaka|first2=M|last3=Vandenbon|first3=A|last4=Saitoh|first4=T|last5=Kawasaki|first5=T|last6=Kondo|first6=T|last7=Yokoyama|first7=KK|last8=Kidoya|first8=H|last9=Takakura|first9=N|last10=Standley|first10=D|last11=Takeuchi|first11=O|last12=Akira|first12=S|title=The transcription factor Jdp2 controls bone homeostasis and antibacterial immunity by regulating osteoclast and neutrophil differentiation.|journal=Immunity|date=14 December 2012|volume=37|issue=6|pages=1024-36|pmid=23200825}}</ref> and cell proliferation, and commit to cell cycle arrest because of AP-1 repression <ref name=#6 />. TransgenicJDP2 mice display atrial dilation <ref>{{cite journal|last1=Kehat|first1=I|last2=Heinrich|first2=R|last3=Ben-Izhak|first3=O|last4=Miyazaki|first4=H|last5=Gutkind|first5=JS|last6=Aronheim|first6=A|title=Inhibition of basic leucine zipper transcription is a major mediator of atrial dilatation.|journal=Cardiovascular Research|date=1 June 2006|volume=70|issue=3|pages=543-54|pmid=16631626}}</ref> and myocardial hypertrophy (26)<ref>{{cite journal|last1=Kehat|first1=I|last2=Hasin|first2=T|last3=Aronheim|first3=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|date=October 2006|volume=1080|pages=97-109|pmid=17132778}}</ref>.

===Dimer formation and interacting molecules===
JDP2 functions as a transcription 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, Fra2, ATF2 <ref name=#1 /><ref name=#2>{{cite journal|last1=Jin|first1=C|last2=Ugai|first2=H|last3=Song|first3=J|last4=Murata|first4=T|last5=Nili|first5=F|last6=Sun|first6=K|last7=Horikoshi|first7=M|last8=Yokoyama|first8=KK|title=Identification of mouse Jun dimerization protein 2 as a novel repressor of ATF-2.|journal=FEBS Letters|date=26 January 2001|volume=489|issue=1|pages=34-41|pmid=11231009}}</ref><ref name=#20 /> 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 <ref name=#27>{{cite journal|last1=Chérasse|first1=Y|last2=Chaveroux|first2=C|last3=Jousse|first3=C|last4=Maurin|first4=AC|last5=Carraro|first5=V|last6=Parry|first6=L|last7=Fafournoux|first7=P|last8=Bruhat|first8=A|title=Role of the repressor JDP2 in the amino acid-regulated transcription of CHOP.|journal=FEBS Letters|date=30 April 2008|volume=582|issue=10|pages=1537-41|pmid=18396163}}</ref><ref>{{cite journal|last1=Weidenfeld-Baranboim|first1=K|last2=Bitton-Worms|first2=K|last3=Aronheim|first3=A|title=TRE-dependent transcription activation by JDP2-CHOP10 association.|journal=Nucleic Acids Research|date=June 2008|volume=36|issue=11|pages=3608-19|pmid=18463134}}</ref>. In addition, JDP2 has been shown to directly associate with the progesterone receptor (PR) and functionally acts as a coactivator of progesterone-dependent PR-mediated gene transcription <ref>{{cite journal|last1=Hill|first1=KK|last2=Roemer|first2=SC|last3=Jones|first3=DN|last4=Churchill|first4=ME|last5=Edwards|first5=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|date=4 September 2009|volume=284|issue=36|pages=24415-24|pmid=19553667}}</ref><ref>{{cite journal|last1=Wardell|first1=SE|last2=Boonyaratanakornkit|first2=V|last3=Adelman|first3=JS|last4=Aronheim|first4=A|last5=Edwards|first5=DP|title=Jun dimerization protein 2 functions as a progesterone receptor N-terminal domain coactivator.|journal=Molecular and Cellular Biology|date=August 2002|volume=22|issue=15|pages=5451-66|pmid=12101239}}</ref><ref>{{cite journal|last1=Edwards|first1=DP|last2=Wardell|first2=SE|last3=Boonyaratanakornkit|first3=V|title=Progesterone receptor interacting coregulatory proteins and cross talk with cell signaling pathways.|journal=The Journal of Steroid Biochemistry and Molecular Biology|date=December 2002|volume=83|issue=1-5|pages=173-86|pmid=12650714}}</ref>. Other proteins such as interferon regulatory factor-2-binding protein-1 (IRF2-BP1) (16)<ref name=#16 />, CCAAT/enhancer-binding protein gamma (C/EBPγ) <ref>{{cite journal|last1=Broder|first1=YC|last2=Katz|first2=S|last3=Aronheim|first3=A|title=The ras recruitment system, a novel approach to the study of protein-protein interactions.|journal=Current Biology|date=8 October 1998|volume=8|issue=20|pages=1121-4|pmid=9778531}}</ref>, HDAC 3 and HDAC 6 <ref name=#20 /><ref name="#22 MCB2002" /> 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="#22 MCB2002" /> and adipocyte differentiation <ref>{{cite journal|last1=Nakade|first1=K|last2=Pan|first2=J|last3=Yoshiki|first3=A|last4=Ugai|first4=H|last5=Kimura|first5=M|last6=Liu|first6=B|last7=Li|first7=H|last8=Obata|first8=Y|last9=Iwama|first9=M|last10=Itohara|first10=S|last11=Murata|first11=T|last12=Yokoyama|first12=KK|title=JDP2 suppresses adipocyte differentiation by regulating histone acetylation.|journal=Cell Death and Differentiation|date=August 2007|volume=14|issue=8|pages=1398-405|pmid=17464331}}</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 (34)<ref name=#34>{{cite journal|last1=Ostrovsky|first1=O|last2=Bengal|first2=E|last3=Aronheim|first3=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|date=18 October 2002|volume=277|issue=42|pages=40043-54|pmid=12171923}}</ref>. It is also reported that JDP2 plays an important role in the RANK-mediated osteoclast differentiation (35)<ref name="#35 JEM">{{cite journal|last1=Kawaida|first1=R|last2=Ohtsuka|first2=T|last3=Okutsu|first3=J|last4=Takahashi|first4=T|last5=Kadono|first5=Y|last6=Oda|first6=H|last7=Hikita|first7=A|last8=Nakamura|first8=K|last9=Tanaka|first9=S|last10=Furukawa|first10=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|date=21 April 2003|volume=197|issue=8|pages=1029-35|pmid=12707301}}</ref>. Further, JDP2 is involved in neutrophil differentiation <ref name="#24 Immunity" /> and transcription factor Tbx3-mediated osteoclastogenesis <ref>{{cite journal|last1=Yao|first1=C|last2=Yao|first2=GQ|last3=Sun|first3=BH|last4=Zhang|first4=C|last5=Tommasini|first5=SM|last6=Insogna|first6=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|date=7 March 2014|volume=289|issue=10|pages=6775-90|pmid=24394418}}</ref> for host defense and bone homeostasis <ref name="#24 Immunity" />. Methylome mapping suggests that JDP2 plays a role in cell progenitor differentiation of megakaryocytes <ref>{{cite journal|last1=Ji|first1=H|last2=Ehrlich|first2=LI|last3=Seita|first3=J|last4=Murakami|first4=P|last5=Doi|first5=A|last6=Lindau|first6=P|last7=Lee|first7=H|last8=Aryee|first8=MJ|last9=Irizarry|first9=RA|last10=Kim|first10=K|last11=Rossi|first11=DJ|last12=Inlay|first12=MA|last13=Serwold|first13=T|last14=Karsunky|first14=H|last15=Ho|first15=L|last16=Daley|first16=GQ|last17=Weissman|first17=IL|last18=Feinberg|first18=AP|title=Comprehensive methylome map of lineage commitment from haematopoietic progenitors.|journal=Nature|date=16 September 2010|volume=467|issue=7313|pages=338-42|pmid=20720541}}</ref>.

===Regulation of cell cycle and p53 signaling===
JDP2 induces cell cycle arrest through cyclin D <ref name=#34 />, p53, and cyclin A <ref name=#6 /> transcription, by increasing JUNB, JUND, and Fra2, and by decreasing c-JUN through the loss of p27kip1 <ref name="#44 JBC Suppressor gene">{{cite journal|last1=Heinrich|first1=R|last2=Livne|first2=E|last3=Ben-Izhak|first3=O|last4=Aronheim|first4=A|title=The c-Jun dimerization protein 2 inhibits cell transformation and acts as a tumor suppressor gene.|journal=The Journal of Biological Chemistry|date=13 February 2004|volume=279|issue=7|pages=5708-15|pmid=14627710}}</ref>. JDP2 downregulates Trp53 transcription, which promotes leukemogenesis <ref name=#45>{{cite journal|last1=van der Weyden|first1=L|last2=Rust|first2=AG|last3=McIntyre|first3=RE|last4=Robles-Espinoza|first4=CD|last5=del Castillo Velasco-Herrera|first5=M|last6=Strogantsev|first6=R|last7=Ferguson-Smith|first7=AC|last8=McCarthy|first8=S|last9=Keane|first9=TM|last10=Arends|first10=MJ|last11=Adams|first11=DJ|title=Jdp2 downregulates Trp53 transcription to promote leukaemogenesis in the context of Trp53 heterozygosity.|journal=Oncogene|date=17 January 2013|volume=32|issue=3|pages=397-402|pmid=22370638}}</ref>. Mouse p53 protein negatively regulates the JDP2 promoter in F9 cells <ref name=#46>{{cite journal|last1=Xu|first1=Y|last2=Jin|first2=C|last3=Liu|first3=Z|last4=Pan|first4=J|last5=Li|first5=H|last6=Zhang|first6=Z|last7=Bi|first7=S|last8=Yokoyama|first8=KK|title=Cloning and characterization of the mouse JDP2 gene promoter reveal negative regulation by p53.|journal=Biochemical and Biophysical Research Communications|date=8 August 2014|volume=450|issue=4|pages=1531-6|pmid=25026555}}</ref> as part of the JDP2˗p53 autoregulatory circuit. By contrast, JDP2-knockout mice exhibit in downregulation of p53 and p21 proteins <ref name=#6 />.

===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|last1=Lerdrup|first1=M|last2=Holmberg|first2=C|last3=Dietrich|first3=N|last4=Shaulian|first4=E|last5=Herdegen|first5=T|last6=Jäättelä|first6=M|last7=Kallunki|first7=T|title=Depletion of the AP-1 repressor JDP2 induces cell death similar to apoptosis.|journal=Biochimica et Biophysica Acta|date=15 August 2005|volume=1745|issue=1|pages=29-37|pmid=16026868}}</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|last1=Piu|first1=F|last2=Aronheim|first2=A|last3=Katz|first3=S|last4=Karin|first4=M|title=AP-1 repressor protein JDP-2: inhibition of UV-mediated apoptosis through p53 down-regulation.|journal=Molecular and Cellular Biology|date=May 2001|volume=21|issue=9|pages=3012-24|pmid=11287607}}</ref>. Heart-specific JDP2 overexpression protects cardiomyocytes against hypertrophic growth and TGFβ–induced apoptosis <ref>{{cite journal|last1=Hill|first1=C|last2=Würfel|first2=A|last3=Heger|first3=J|last4=Meyering|first4=B|last5=Schlüter|first5=KD|last6=Weber|first6=M|last7=Ferdinandy|first7=P|last8=Aronheim|first8=A|last9=Schulz|first9=R|last10=Euler|first10=G|title=Inhibition of AP-1 signaling by JDP2 overexpression protects cardiomyocytes against hypertrophy and apoptosis induction.|journal=Cardiovascular Research|date=1 July 2013|volume=99|issue=1|pages=121-8|pmid=23612584}}</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 the Polycomb-repressive complexes (PRC-1 and PRC-2) to the promoters at the p16Ink4a locus <ref name=#18 /><ref name="#23 JBC" />.

===Oxidative stress and antioxidative response===
The increased accumulation of intracellular 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=#7 /><ref>{{cite journal|last1=Wang|first1=SW|last2=Lee|first2=JK|last3=Ku|first3=CC|last4=Chiou|first4=SS|last5=Steve Lin|first5=CL|last6=Ho|first6=MF|last7=Wu|first7=DC|last8=Yokoyama|first8=KK|title=Jun dimerization protein 2 in oxygen restriction; control of senescence.|journal=Current Pharmaceutical Design|date=2011|volume=17|issue=22|pages=2278-89|pmid=21736542}}</ref><ref>{{cite journal|pmid=21736542}}</ref><ref name=#42>{{cite journal|last1=Tanigawa|first1=S|last2=Lee|first2=CH|last3=Lin|first3=CS|last4=Ku|first4=CC|last5=Hasegawa|first5=H|last6=Qin|first6=S|last7=Kawahara|first7=A|last8=Korenori|first8=Y|last9=Miyamori|first9=K|last10=Noguchi|first10=M|last11=Lee|first11=LH|last12=Lin|first12=YC|last13=Steve Lin|first13=CL|last14=Nakamura|first14=Y|last15=Jin|first15=C|last16=Yamaguchi|first16=N|last17=Eckner|first17=R|last18=Hou|first18=DX|last19=Yokoyama|first19=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|date=14 November 2013|volume=4|pages=e921|pmid=24232097}}</ref>. Furthermore, JDP2 binds directly to the antioxidant responsive element (ARE) core sequence, associates with Nrf2 and 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 HO-1 and NQO-1 <ref name=#42 />. 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=#6 /><ref name=#7 />, 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 cells (iPSC)-like cells. This iPSC-like cells expressed stem cell-like characteristics including alkaline phosphatase activity and some stem cell markers, including SSEA3, SSEA4 and Tra-1-60 <ref name=#7 />. Later, another study also showed that JDP2 can substitute Oct4 to generate iPSCs with Klf4, Sox2 and Myc (KSM) or KS from somatic cells <ref>{{cite journal|last1=Liu|first1=J|last2=Han|first2=Q|last3=Peng|first3=T|last4=Peng|first4=M|last5=Wei|first5=B|last6=Li|first6=D|last7=Wang|first7=X|last8=Yu|first8=S|last9=Yang|first9=J|last10=Cao|first10=S|last11=Huang|first11=K|last12=Hutchins|first12=AP|last13=Liu|first13=H|last14=Kuang|first14=J|last15=Zhou|first15=Z|last16=Chen|first16=J|last17=Wu|first17=H|last18=Guo|first18=L|last19=Chen|first19=Y|last20=Chen|first20=Y|last21=Li|first21=X|last22=Wu|first22=H|last23=Liao|first23=B|last24=He|first24=W|last25=Song|first25=H|last26=Yao|first26=H|last27=Pan|first27=G|last28=Chen|first28=J|last29=Pei|first29=D|title=The oncogene c-Jun impedes somatic cell reprogramming.|journal=Nature Cell bBiology|date=July 2015|volume=17|issue=7|pages=856-67|pmid=26098572}}</ref>. Moreover, they showed that JDP2 anchors five non-Yamanaka factors (Id1, Jhdm1b, 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 NIH3T3 cells and tumor development in xenografts transplanted into SCID mice <ref name="#44 JBC Suppressor gene" />. Constitutive expression of JDP2 in rhabdomyosarcoma cells reduced their tumorigenic characteristics <ref name=#34 />. On the other hand, JDP2 induces partial oncogenic transformation of chicken embryonic fibroblasts <ref>{{cite journal|last1=Blazek|first1=E|last2=Wasmer|first2=S|last3=Kruse|first3=U|last4=Aronheim|first4=A|last5=Aoki|first5=M|last6=Vogt|first6=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|date=10 April 2003|volume=22|issue=14|pages=2151-9|pmid=12687017}}</ref>. Studies using high throughput viral insertional mutagenesis analysis also revealed that JDP2 functions as an oncogene <ref name=#5 /><ref name=#45 /><ref>{{cite journal|last1=Hwang|first1=HC|last2=Martins|first2=CP|last3=Bronkhorst|first3=Y|last4=Randel|first4=E|last5=Berns|first5=A|last6=Fero|first6=M|last7=Clurman|first7=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|date=20 August 2002|volume=99|issue=17|pages=11293-8|pmid=12151601}}</ref><ref>{{cite journal|last1=Stewart|first1=M|last2=Mackay|first2=N|last3=Hanlon|first3=L|last4=Blyth|first4=K|last5=Scobie|first5=L|last6=Cameron|first6=E|last7=Neil|first7=JC|title=Insertional mutagenesis reveals progression genes and checkpoints in MYC/Runx2 lymphomas.|journal=Cancer Research|date=1 June 2007|volume=67|issue=11|pages=5126-33|pmid=17545590}}</ref><ref>{{cite journal|last1=Rasmussen|first1=MH|last2=Wang|first2=B|last3=Wabl|first3=M|last4=Nielsen|first4=AL|last5=Pedersen|first5=FS|title=Activation of alternative Jdp2 promoters and functional protein isoforms in T-cell lymphomas by retroviral insertion mutagenesis.|journal=Nucleic Acids Research|date=August 2009|volume=37|issue=14|pages=4657-71|pmid=19502497}}</ref><ref>{{cite journal|last1=Rasmussen|first1=MH|last2=Ballarín-González|first2=B|last3=Liu|first3=J|last4=Lassen|first4=LB|last5=Füchtbauer|first5=A|last6=Füchtbauer|first6=EM|last7=Nielsen|first7=AL|last8=Pedersen|first8=FS|title=Antisense transcription in gammaretroviruses as a mechanism of insertional activation of host genes.|journal=Journal of Virology|date=April 2010|volume=84|issue=8|pages=3780-8|pmid=20130045}}</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|last1=Bitton-Worms|first1=K|last2=Pikarsky|first2=E|last3=Aronheim|first3=A|title=The AP-1 repressor protein, JDP2, potentiates hepatocellular carcinoma in mice.|journal=Molecular Cancer|date=9 March 2010|volume=9|pages=54|pmid=20214788}}</ref>.

==Cancer and disease markers==
JDP2 shows the gene amplification of head and neck squamous cell carcinoma <ref>{{cite journal|last1=Järvinen|first1=AK|last2=Autio|first2=R|last3=Kilpinen|first3=S|last4=Saarela|first4=M|last5=Leivo|first5=I|last6=Grénman|first6=R|last7=Mäkitie|first7=AA|last8=Monni|first8=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|date=June 2008|volume=47|issue=6|pages=500-9|pmid=18314910}}</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|last1=Yuanhong|first1=X|last2=Feng|first2=X|last3=Qingchang|first3=L|last4=Jianpeng|first4=F|last5=Zhe|first5=L|last6=Kejian|first6=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|date=2009|volume=25|issue=3|pages=136-40|pmid=20677166}}</ref>. In addition, JDP2 overexpression reverses the epithelial-to-mesenchymal transition (EMT) induced by co-treatment with TGF-β1 and EGF in human pancreatic BxPC3 cells, suggesting that JDP2 may be a molecular target for pancreatic carcinoma intervention <ref>{{cite journal|last1=Liu|first1=Z|last2=Du|first2=R|last3=Long|first3=J|last4=Dong|first4=A|last5=Fan|first5=J|last6=Guo|first6=K|last7=Xu|first7=Y|title=JDP2 inhibits the epithelial-to-mesenchymal transition in pancreatic cancer BxPC3 cells.|journal=Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine|date=October 2012|volume=33|issue=5|pages=1527-34|pmid=22535371}}</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 HF (55)<ref>{{cite journal|last1=Maciejak|first1=A|last2=Kiliszek|first2=M|last3=Michalak|first3=M|last4=Tulacz|first4=D|last5=Opolski|first5=G|last6=Matlak|first6=K|last7=Dobrzycki|first7=S|last8=Segiet|first8=A|last9=Gora|first9=M|last10=Burzynska|first10=B|title=Gene expression profiling reveals potential prognostic biomarkers associated with the progression of heart failure.|journal=Genome Medicine|date=2015|volume=7|issue=1|pages=26|pmid=25984239}}</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=#34 /> and gene for galection-7 <ref>{{cite journal|last1=Barkan|first1=B|last2=Cox|first2=AD|last3=Kloog|first3=Y|title=Ras inhibition boosts galectin-7 at the expense of galectin-1 to sensitize cells to apoptosis.|journal=Oncotarget|date=February 2013|volume=4|issue=2|pages=256-68|pmid=23530091}}</ref>. JDP2 functionally associated with HDAC3 and acts as a repressor to inhibit the amino acid regulation of CHOP transcription <ref name=#27 />. JDP2 and ATF3 are involved in recruiting HDACs to the ATF3 promoter region resulting in transcriptional repression of ATF3 <ref name=#20 />. 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 <ref>{{cite journal|last1=Murata|first1=T|last2=Noda|first2=C|last3=Saito|first3=S|last4=Kawashima|first4=D|last5=Sugimoto|first5=A|last6=Isomura|first6=H|last7=Kanda|first7=T|last8=Yokoyama|first8=KK|last9=Tsurumi|first9=T|title=Involvement of Jun dimerization protein 2 (JDP2) in the maintenance of Epstein-Barr virus latency.|journal=The Journal of Biological Chemistry|date=24 June 2011|volume=286|issue=25|pages=22007-16|pmid=21525011}}</ref>.


==Interactions==
==Interactions==

Revision as of 10:01, 10 January 2016

Template:PBB Jun dimerization protein 2 is a protein that in humans is encoded by the JDP2 gene.[1][2][3][4]

The Jun dimerization protein is a member of the AP-1 family of transcription factors.[2]

Jun dimerization protein 2 (JUNDM2) is a member of the activating protein-1 (AP-1) family of transcription factors, was found by the Sos recruitment system, to dimerize with c-Jun to repress AP-1-mediated activation (1)[5]. It was later identified by the yeast-two hybrid system to bind to activation transcription factor 2 (ATF2) to repress ATF-mediated transcriptional activation (2)[6]. JDP2 regulates 12-O-tetradecanoylphorbol-13-acetate (TPA) response element (TRE)- and cAMP-responsive element (CRE)-dependent transcription (3)[7]. 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) (4)[8][9], which is located at about 250 kbp in the Fos-JDP2-BATF locus (5)[10]. JDP2 is expressed ubiquitously but is detected mainly in the cerebellum, brain, lung, and testis (6, 7)[11][12]. The single nucleotide polymorphism (SNP) was detected in Japanese, Korean, and Dutch cohorts, belongs to the family of intracranial aneurysms (8)[13]. The alternative splicing of JDP2 generates at least two isoforms (5, 9)[10][14]. The protein JDP2 has 163 amino acids, belongs to the family of basic leucine zippers (bZIP), and shows great homology with the ATF-3 bZIP domain (1, 10)[15][16]. 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 (11)[17], which is located before the DNA-binding domain.

Posttranscriptional and posttranslational modifications

Phosphorylation of the threonine (Thr) residue at position 148 is mediated by c-Jun N-terminal kinase (MAPK8; JNK1) and p38 MAPK (12, 13)[18][19]. Phosphorylated ATF2 inhibits the formation with JDP2 in vitro (14)[20] while phosphorylated JDP2 undergoes proteosomal degradation (15)[21]. It contains putative SUMO modification of lysine (Lys) residue at position 65 (4; http://www.uniprot.org/uniprot/Q8WYK2), and recruits interferon regulatory factor 2 binding protein 1 (IRF2BP1), which acts as an E3 ligase (16)[22]. 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 (13)[19] and doublecortin like protein kinase (17)[23]. Polyubiquitination of JDP2 protein is induced by IRF2BP1 (16)[22]. JDP2 displays histone-binding and histone-chaperone activity (18, 19)[24][25] and inhibition of p300/CBP induced histone acetylation (INHAT) (18, 19)[24][25]. JDP2 recruits histone deacetylase (HDAC) 1, HDAC2 (20, 21)[26][27], HDAC6 (20)[26] and HDAC3 (22)[28]. JDP2 has INHAT activity (11)[17] and inhibits histone methylation in vitro (23)[29].

Function

Phenotypes of gene knockout and transgenic mice

Gene knockout mice have a shorter tail, are smaller, have low neutrophil count [11][30] and cell proliferation, and commit to cell cycle arrest because of AP-1 repression [11]. TransgenicJDP2 mice display atrial dilation [31] and myocardial hypertrophy (26)[32].

Dimer formation and interacting molecules

JDP2 functions as a transcription 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, Fra2, ATF2 [15][33][26] 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 [34][35]. In addition, JDP2 has been shown to directly associate with the progesterone receptor (PR) and functionally acts as a coactivator of progesterone-dependent PR-mediated gene transcription [36][37][38]. Other proteins such as interferon regulatory factor-2-binding protein-1 (IRF2-BP1) (16)[22], CCAAT/enhancer-binding protein gamma (C/EBPγ) [39], HDAC 3 and HDAC 6 [26][28] 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 [28] and adipocyte differentiation [40]. 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 (34)[41]. It is also reported that JDP2 plays an important role in the RANK-mediated osteoclast differentiation (35)[42]. Further, JDP2 is involved in neutrophil differentiation [30] and transcription factor Tbx3-mediated osteoclastogenesis [43] for host defense and bone homeostasis [30]. Methylome mapping suggests that JDP2 plays a role in cell progenitor differentiation of megakaryocytes [44].

Regulation of cell cycle and p53 signaling

JDP2 induces cell cycle arrest through cyclin D [41], p53, and cyclin A [11] transcription, by increasing JUNB, JUND, and Fra2, and by decreasing c-JUN through the loss of p27kip1 [45]. JDP2 downregulates Trp53 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 [11].

Apoptosis and senescence

JDP2 appears to be involved in the inhibition of apoptosis. 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 cellular senescence. JDP2-deficient mouse embryonic fibroblasts are resistant to replicative senescence by recruiting the Polycomb-repressive complexes (PRC-1 and PRC-2) to the promoters at the p16Ink4a locus [24][29].

Oxidative stress and antioxidative response

The increased accumulation of intracellular 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 [12][51][52][53]. Furthermore, JDP2 binds directly to the antioxidant responsive element (ARE) core sequence, associates with Nrf2 and 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 HO-1 and NQO-1 [53]. 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 [11][12], 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 cells (iPSC)-like cells. This iPSC-like cells expressed stem cell-like characteristics including alkaline phosphatase activity and some stem cell markers, including SSEA3, SSEA4 and Tra-1-60 [12]. Later, another study also showed that JDP2 can substitute Oct4 to generate iPSCs with Klf4, Sox2 and Myc (KSM) or KS from somatic cells [54]. Moreover, they showed that JDP2 anchors five non-Yamanaka factors (Id1, Jhdm1b, 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 NIH3T3 cells and tumor development in xenografts transplanted into SCID mice [45]. Constitutive expression of JDP2 in rhabdomyosarcoma cells reduced their tumorigenic characteristics [41]. On the other hand, JDP2 induces partial oncogenic transformation of chicken embryonic fibroblasts [55]. Studies using high throughput viral insertional mutagenesis analysis also revealed that JDP2 functions as an oncogene [10][46][56][57][58][59]. 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 [60].

Cancer and disease markers

JDP2 shows the gene amplification of head and neck squamous cell carcinoma [61]. 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 [62]. In addition, JDP2 overexpression reverses the epithelial-to-mesenchymal transition (EMT) induced by co-treatment with TGF-β1 and EGF in human pancreatic BxPC3 cells, suggesting that JDP2 may be a molecular target for pancreatic carcinoma intervention [63]. 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 HF (55)[64].

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 [41] and gene for galection-7 [65]. JDP2 functionally associated with HDAC3 and acts as a repressor to inhibit the amino acid regulation of CHOP transcription [34]. JDP2 and ATF3 are involved in recruiting HDACs to the ATF3 promoter region resulting in transcriptional repression of ATF3 [26]. 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 [66].

Interactions

JDP2 (gene) has been shown to interact with Activating transcription factor 2.[67]

References

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