Full text data of JUN
JUN
[Confidence: low (only semi-automatic identification from reviews)]
Transcription factor AP-1 (Activator protein 1; AP1; Proto-oncogene c-Jun; V-jun avian sarcoma virus 17 oncogene homolog; p39)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Transcription factor AP-1 (Activator protein 1; AP1; Proto-oncogene c-Jun; V-jun avian sarcoma virus 17 oncogene homolog; p39)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P05412
ID JUN_HUMAN Reviewed; 331 AA.
AC P05412; Q96G93;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1989, sequence version 2.
DT 22-JAN-2014, entry version 184.
DE RecName: Full=Transcription factor AP-1;
DE AltName: Full=Activator protein 1;
DE Short=AP1;
DE AltName: Full=Proto-oncogene c-Jun;
DE AltName: Full=V-jun avian sarcoma virus 17 oncogene homolog;
DE AltName: Full=p39;
GN Name=JUN;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3194415; DOI=10.1073/pnas.85.23.9148;
RA Hattori K., Angel P., le Beau M.M., Karin M.;
RT "Structure and chromosomal localization of the functional intronless
RT human JUN protooncogene.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:9148-9152(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2825349; DOI=10.1126/science.2825349;
RA Bohmann D., Bos T.J., Admon A., Nishimura T., Vogt P.K., Tjian R.;
RT "Human proto-oncogene c-jun encodes a DNA binding protein with
RT structural and functional properties of transcription factor AP-1.";
RL Science 238:1386-1392(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=B-cell, Ovary, Testis, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PHOSPHORYLATION AT THR-239; SER-243 AND SER-249 BY GSK3B.
RX PubMed=1846781; DOI=10.1016/0092-8674(91)90241-P;
RA Boyle W.J., Smeal T., Defize L.H., Angel P., Woodgett J.R., Karin M.,
RA Hunter T.;
RT "Activation of protein kinase C decreases phosphorylation of c-Jun at
RT sites that negatively regulate its DNA-binding activity.";
RL Cell 64:573-584(1991).
RN [8]
RP PHOSPHORYLATION AT SER-249.
RX PubMed=8464713; DOI=10.1093/nar/21.5.1289;
RA Bannister A.J., Gottlieb T.M., Kouzarides T., Jackson S.P.;
RT "c-Jun is phosphorylated by the DNA-dependent protein kinase in vitro;
RT definition of the minimal kinase recognition motif.";
RL Nucleic Acids Res. 21:1289-1295(1993).
RN [9]
RP PHOSPHORYLATION BY CAMK4.
RX PubMed=8855261; DOI=10.1073/pnas.93.20.10803;
RA Enslen H., Tokumitsu H., Stork P.J., Davis R.J., Soderling T.R.;
RT "Regulation of mitogen-activated protein kinases by a
RT calcium/calmodulin-dependent protein kinase cascade.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:10803-10808(1996).
RN [10]
RP INTERACTION WITH TCF20.
RX PubMed=8663478; DOI=10.1074/jbc.271.30.18231;
RA Kirstein M., Sanz L., Moscat J., Diaz-Meco M.T., Saus J.;
RT "Cross-talk between different enhancer elements during mitogenic
RT induction of the human stromelysin-1 gene.";
RL J. Biol. Chem. 271:18231-18236(1996).
RN [11]
RP INTERACTION WITH COPS5.
RX PubMed=8837781; DOI=10.1038/383453a0;
RA Claret F.-X., Hibi M., Dhut S., Toda T., Karin M.;
RT "A new group of conserved coactivators that increase the specificity
RT of AP-1 transcription factors.";
RL Nature 383:453-457(1996).
RN [12]
RP IDENTIFICATION AS A COMPONENT OF THE SMAD3/SMAD4/JUN/FOS COMPLEX, AND
RP INTERACTION WITH SMAD3.
RX PubMed=9732876; DOI=10.1038/29814;
RA Zhang Y., Feng X.H., Derynck R.;
RT "Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-
RT induced transcription.";
RL Nature 394:909-913(1998).
RN [13]
RP INTERACTION WITH SPIB.
RX PubMed=10196196; DOI=10.1074/jbc.274.16.11115;
RA Rao S., Matsumura A., Yoon J., Simon M.C.;
RT "SPI-B activates transcription via a unique proline, serine, and
RT threonine domain and exhibits DNA binding affinity differences from
RT PU.1.";
RL J. Biol. Chem. 274:11115-11124(1999).
RN [14]
RP INTERACTION WITH ATF7, AND MUTAGENESIS OF SER-63 AND SER-73.
RX PubMed=10376527; DOI=10.1038/sj.onc.1202723;
RA De Graeve F., Bahr A., Sabapathy K.T., Hauss C., Wagner E.F.,
RA Kedinger C., Chatton B.;
RT "Role of the ATFa/JNK2 complex in Jun activation.";
RL Oncogene 18:3491-3500(1999).
RN [15]
RP INTERACTION WITH SMAD3 IN THE SMAD3/SMAD4/JUN/FOS COMPLEX,
RP DNA-BINDING, FUNCTION, AND MUTAGENESIS OF ARG-272.
RX PubMed=10995748; DOI=10.1074/jbc.M004731200;
RA Qing J., Zhang Y., Derynck R.;
RT "Structural and functional characterization of the transforming growth
RT factor-beta -induced Smad3/c-Jun transcriptional cooperativity.";
RL J. Biol. Chem. 275:38802-38812(2000).
RN [16]
RP ACETYLATION AT LYS-271 BY EP300.
RX PubMed=11689449; DOI=10.1093/emboj/20.21.6095;
RA Vries R.G., Prudenziati M., Zwartjes C., Verlaan M., Kalkhoven E.,
RA Zantema A.;
RT "A specific lysine in c-Jun is required for transcriptional repression
RT by E1A and is acetylated by p300.";
RL EMBO J. 20:6095-6103(2001).
RN [17]
RP INTERACTION WITH BATF3.
RX PubMed=12087103; DOI=10.1074/jbc.M205048200;
RA Bower K.E., Zeller R.W., Wachsman W., Martinez T., McGuire K.L.;
RT "Correlation of transcriptional repression by p21(SNFT) with changes
RT in DNA.NF-AT complex interactions.";
RL J. Biol. Chem. 277:34967-34977(2002).
RN [18]
RP INTERACTION WITH BATF3.
RX PubMed=15467742; DOI=10.1038/sj.onc.1208109;
RA Bower K.E., Fritz J.M., McGuire K.L.;
RT "Transcriptional repression of MMP-1 by p21SNFT and reduced in vitro
RT invasiveness of hepatocarcinoma cells.";
RL Oncogene 23:8805-8814(2004).
RN [19]
RP FUNCTION, AND PHOSPHORYLATION BY HIPK3.
RX PubMed=17210646; DOI=10.1128/MCB.02253-06;
RA Lan H.-C., Li H.-J., Lin G., Lai P.-Y., Chung B.-C.;
RT "Cyclic AMP stimulates SF-1-dependent CYP11A1 expression through
RT homeodomain-interacting protein kinase 3-mediated Jun N-terminal
RT kinase and c-Jun phosphorylation.";
RL Mol. Cell. Biol. 27:2027-2036(2007).
RN [20]
RP INTERACTION WITH SP1.
RX PubMed=16478997; DOI=10.1128/MCB.26.5.1770-1785.2006;
RA Hung J.J., Wang Y.T., Chang W.C.;
RT "Sp1 deacetylation induced by phorbol ester recruits p300 to activate
RT 12(S)-lipoxygenase gene transcription.";
RL Mol. Cell. Biol. 26:1770-1785(2006).
RN [21]
RP PHOSPHORYLATION AT SER-63 AND SER-73.
RX PubMed=17804415; DOI=10.1074/jbc.M702791200;
RA Wang L., Dai W., Lu L.;
RT "Stress-induced c-Jun activation mediated by Polo-like kinase 3 in
RT corneal epithelial cells.";
RL J. Biol. Chem. 282:32121-32127(2007).
RN [22]
RP PHOSPHORYLATION AT SER-63 AND SER-73.
RX PubMed=18650425; DOI=10.1074/jbc.M801326200;
RA Wang L., Gao J., Dai W., Lu L.;
RT "Activation of Polo-like kinase 3 by hypoxic stresses.";
RL J. Biol. Chem. 283:25928-25935(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-58; SER-63; THR-239 AND
RP SER-243, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-63 AND SER-243, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [26]
RP INTERACTION WITH RNF187.
RX PubMed=20852630; DOI=10.1038/ncb2098;
RA Davies C.C., Chakraborty A., Cipriani F., Haigh K., Haigh J.J.,
RA Behrens A.;
RT "Identification of a co-activator that links growth factor signalling
RT to c-Jun/AP-1 activation.";
RL Nat. Cell Biol. 12:963-972(2010).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-63, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [28]
RP PHOSPHORYLATION AT THR-2; THR-8; THR-89; THR-93 AND THR-286, AND
RP MUTAGENESIS OF THR-2; THR-8; THR-89; THR-93 AND THR-286.
RX PubMed=21177766; DOI=10.1093/carcin/bgq271;
RA Li T., Zhang J., Zhu F., Wen W., Zykova T., Li X., Liu K., Peng C.,
RA Ma W., Shi G., Dong Z., Bode A.M., Dong Z.;
RT "P21-activated protein kinase (PAK2)-mediated c-Jun phosphorylation at
RT 5 threonine sites promotes cell transformation.";
RL Carcinogenesis 32:659-666(2011).
RN [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-58 AND SER-63, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [30]
RP PHOSPHORYLATION AT SER-243, AND MUTAGENESIS OF SER-243.
RX PubMed=22307329; DOI=10.1172/JCI60818;
RA Taira N., Mimoto R., Kurata M., Yamaguchi T., Kitagawa M., Miki Y.,
RA Yoshida K.;
RT "DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle
RT progression in human cancer cells.";
RL J. Clin. Invest. 122:859-872(2012).
RN [31]
RP INTERACTION WITH RNF187.
RX PubMed=23624934; DOI=10.1038/emboj.2013.98;
RA Davies C.C., Chakraborty A., Diefenbacher M.E., Skehel M., Behrens A.;
RT "Arginine methylation of the c-Jun coactivator RACO-1 is required for
RT c-Jun/AP-1 activation.";
RL EMBO J. 32:1556-1567(2013).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (3.05 ANGSTROMS) OF 257-313 OF COMPLEX WITH FOS.
RX PubMed=7816143; DOI=10.1038/373257a0;
RA Glover J.N., Harrison S.C.;
RT "Crystal structure of the heterodimeric bZIP transcription factor c-
RT Fos-c-Jun bound to DNA.";
RL Nature 373:257-261(1995).
RN [33]
RP STRUCTURE BY NMR OF 276-314.
RX PubMed=8662824; DOI=10.1074/jbc.271.23.13663;
RA Junius F.K., O'Donoghue S.I., Nilges M., Weiss A.S., King G.F.;
RT "High resolution NMR solution structure of the leucine zipper domain
RT of the c-Jun homodimer.";
RL J. Biol. Chem. 271:13663-13667(1996).
CC -!- FUNCTION: Transcription factor that recognizes and binds to the
CC enhancer heptamer motif 5'-TGA[CG]TCA-3'. Promotes activity of
CC NR5A1 when phosphorylated by HIPK3 leading to increased
CC steroidogenic gene expression upon cAMP signaling pathway
CC stimulation.
CC -!- SUBUNIT: Heterodimer with either FOS or BATF3 or ATF7. The
CC ATF7/JUN heterodimer is essential for ATF7 transactivation
CC activity. Interacts with DSIPI; the interaction inhibits the
CC binding of active AP1 to its target DNA (By similarity). Interacts
CC with HIVEP3 and MYBBP1A (By similarity). Interacts with SP1, SPIB
CC and TCF20. Interacts with COPS5; the interaction leads indirectly
CC to its phosphorylation. Component of the
CC SMAD3/SMAD4/JUN/FOS/complex which forms at the AP1 promoter site.
CC The SMAD3/SMAD4 heterodimer acts syngernistically with the JUN/FOS
CC heterodimer to activate transcription in response to TGF-beta.
CC Interacts (via its basic DNA binding and leucine zipper domains)
CC with SMAD3 (via an N-terminal domain); the interaction is required
CC for TGF-beta-mediated transactivation of the
CC SMAD3/SMAD4/JUN/FOS/complex. Interacts with methylated RNF187.
CC Binds to HIPK3.
CC -!- INTERACTION:
CC Q06481:APLP2; NbExp=3; IntAct=EBI-852823, EBI-79306;
CC P05067:APP; NbExp=2; IntAct=EBI-852823, EBI-77613;
CC P15336:ATF2; NbExp=5; IntAct=EBI-852823, EBI-1170906;
CC Q8IWZ6:BBS7; NbExp=3; IntAct=EBI-852823, EBI-1806001;
CC Q99966:CITED1; NbExp=2; IntAct=EBI-852823, EBI-2624951;
CC O43889:CREB3; NbExp=4; IntAct=EBI-852823, EBI-625002;
CC P14921:ETS1; NbExp=3; IntAct=EBI-852823, EBI-913209;
CC P01100:FOS; NbExp=21; IntAct=EBI-852823, EBI-852851;
CC P07900:HSP90AA1; NbExp=2; IntAct=EBI-852823, EBI-296047;
CC Q8WQG9:jnk-1 (xeno); NbExp=3; IntAct=EBI-852823, EBI-321822;
CC P52292:KPNA2; NbExp=2; IntAct=EBI-852823, EBI-349938;
CC P53779:MAPK10; NbExp=2; IntAct=EBI-852823, EBI-713543;
CC P45983:MAPK8; NbExp=4; IntAct=EBI-852823, EBI-286483;
CC P45983-1:MAPK8; NbExp=2; IntAct=EBI-852823, EBI-288687;
CC Q9UPY8:MAPRE3; NbExp=3; IntAct=EBI-852823, EBI-726739;
CC Q00987:MDM2; NbExp=3; IntAct=EBI-852823, EBI-389668;
CC P48634:PRRC2A; NbExp=2; IntAct=EBI-852823, EBI-347545;
CC Q9NRL3:STRN4; NbExp=3; IntAct=EBI-852823, EBI-717245;
CC Q99986:VRK1; NbExp=4; IntAct=EBI-852823, EBI-1769146;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- PTM: Phosphorylated by CaMK4 and PRKDC; phosphorylation enhances
CC the transcriptional activity. Phosphorylated by HIPK3.
CC Phosphorylated by DYRK2 at Ser-243; this primes the protein for
CC subsequent phosphorylation by GSK3B at Thr-239. Phosphorylated at
CC Thr-239, Ser-243 and Ser-249 by GSK3B; phosphorylation reduces its
CC ability to bind DNA. Phosphorylated by PAK2 at Thr-2, Thr-8, Thr-
CC 89, Thr-93 and Thr-286 thereby promoting JUN-mediated cell
CC proliferation and transformation. Phosphorylated by PLK3 following
CC hypoxia or UV irradiation, leading to increase DNA-binding
CC activity.
CC -!- PTM: Acetylated at Lys-271 by EP300.
CC -!- SIMILARITY: Belongs to the bZIP family. Jun subfamily.
CC -!- SIMILARITY: Contains 1 bZIP (basic-leucine zipper) domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/JUNID151.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/jun/";
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DR EMBL; J04111; AAA59197.1; -; Genomic_DNA.
DR EMBL; BT019759; AAV38564.1; -; mRNA.
DR EMBL; AY217548; AAO22993.1; -; Genomic_DNA.
DR EMBL; AL136985; CAC10201.1; -; Genomic_DNA.
DR EMBL; BC002646; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC006175; AAH06175.1; -; mRNA.
DR EMBL; BC009874; AAH09874.2; -; mRNA.
DR EMBL; BC068522; AAH68522.1; -; mRNA.
DR PIR; A31264; TVHUJN.
DR RefSeq; NP_002219.1; NM_002228.3.
DR UniGene; Hs.696684; -.
DR PDB; 1A02; X-ray; 2.70 A; J=254-308.
DR PDB; 1FOS; X-ray; 3.05 A; F/H=254-315.
DR PDB; 1JNM; X-ray; 2.20 A; A/B=254-315.
DR PDB; 1JUN; NMR; -; A/B=276-314.
DR PDB; 1S9K; X-ray; 3.10 A; E=257-308.
DR PDB; 1T2K; X-ray; 3.00 A; C=254-314.
DR PDBsum; 1A02; -.
DR PDBsum; 1FOS; -.
DR PDBsum; 1JNM; -.
DR PDBsum; 1JUN; -.
DR PDBsum; 1S9K; -.
DR PDBsum; 1T2K; -.
DR ProteinModelPortal; P05412; -.
DR SMR; P05412; 257-308.
DR DIP; DIP-5961N; -.
DR IntAct; P05412; 61.
DR MINT; MINT-105756; -.
DR STRING; 9606.ENSP00000360266; -.
DR BindingDB; P05412; -.
DR ChEMBL; CHEMBL2111421; -.
DR DrugBank; DB01169; Arsenic trioxide.
DR DrugBank; DB01029; Irbesartan.
DR DrugBank; DB00570; Vinblastine.
DR PhosphoSite; P05412; -.
DR DMDM; 135298; -.
DR PaxDb; P05412; -.
DR PRIDE; P05412; -.
DR DNASU; 3725; -.
DR Ensembl; ENST00000371222; ENSP00000360266; ENSG00000177606.
DR GeneID; 3725; -.
DR KEGG; hsa:3725; -.
DR UCSC; uc001cze.3; human.
DR CTD; 3725; -.
DR GeneCards; GC01M059246; -.
DR H-InvDB; HIX0000635; -.
DR HGNC; HGNC:6204; JUN.
DR HPA; CAB003801; -.
DR HPA; CAB007780; -.
DR MIM; 165160; gene.
DR neXtProt; NX_P05412; -.
DR PharmGKB; PA30006; -.
DR eggNOG; NOG283376; -.
DR HOGENOM; HOG000006648; -.
DR HOVERGEN; HBG001722; -.
DR InParanoid; P05412; -.
DR KO; K04448; -.
DR OMA; KPHLRNK; -.
DR OrthoDB; EOG75MVXV; -.
DR PhylomeDB; P05412; -.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P05412; -.
DR ChiTaRS; Jun; human.
DR EvolutionaryTrace; P05412; -.
DR GeneWiki; C-jun; -.
DR GenomeRNAi; 3725; -.
DR NextBio; 14583; -.
DR PRO; PR:P05412; -.
DR Bgee; P05412; -.
DR CleanEx; HS_JUN; -.
DR Genevestigator; P05412; -.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005719; C:nuclear euchromatin; IDA:BHF-UCL.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005667; C:transcription factor complex; IEA:Ensembl.
DR GO; GO:0017053; C:transcriptional repressor complex; IEA:Ensembl.
DR GO; GO:0035497; F:cAMP response element binding; IDA:BHF-UCL.
DR GO; GO:0003690; F:double-stranded DNA binding; IEA:Ensembl.
DR GO; GO:0005100; F:Rho GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0001077; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription; IEA:Ensembl.
DR GO; GO:0000980; F:RNA polymerase II distal enhancer sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:0003705; F:RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0001190; F:RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription; IC:BHF-UCL.
DR GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR GO; GO:0031103; P:axon regeneration; IEA:Ensembl.
DR GO; GO:0071277; P:cellular response to calcium ion; IEA:Ensembl.
DR GO; GO:0051365; P:cellular response to potassium ion starvation; IEA:Ensembl.
DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0035026; P:leading edge cell differentiation; IEA:Ensembl.
DR GO; GO:0007612; P:learning; IEA:Ensembl.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0051899; P:membrane depolarization; IEA:Ensembl.
DR GO; GO:0001774; P:microglial cell activation; IEA:Ensembl.
DR GO; GO:0030224; P:monocyte differentiation; IEA:Ensembl.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043922; P:negative regulation by host of viral transcription; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0043392; P:negative regulation of DNA binding; IDA:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0031953; P:negative regulation of protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0003151; P:outflow tract morphogenesis; IEA:Ensembl.
DR GO; GO:0043923; P:positive regulation by host of viral transcription; IDA:UniProtKB.
DR GO; GO:0045740; P:positive regulation of DNA replication; IEA:Ensembl.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IEA:Ensembl.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IEA:Ensembl.
DR GO; GO:0045657; P:positive regulation of monocyte differentiation; IEA:Ensembl.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0051726; P:regulation of cell cycle; IEA:Ensembl.
DR GO; GO:0051090; P:regulation of sequence-specific DNA binding transcription factor activity; TAS:Reactome.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IEA:Ensembl.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0034097; P:response to cytokine stimulus; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0042542; P:response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0009314; P:response to radiation; IEA:Ensembl.
DR GO; GO:0007184; P:SMAD protein import into nucleus; IDA:BHF-UCL.
DR GO; GO:0060395; P:SMAD protein signal transduction; IDA:BHF-UCL.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.880.10; -; 1.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR015558; C_Jun.
DR InterPro; IPR005643; JNK.
DR InterPro; IPR002112; Leuzip_Jun.
DR InterPro; IPR008917; TF_DNA-bd.
DR PANTHER; PTHR11462:SF8; PTHR11462:SF8; 1.
DR Pfam; PF00170; bZIP_1; 1.
DR Pfam; PF03957; Jun; 1.
DR PRINTS; PR00043; LEUZIPPRJUN.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF47454; SSF47454; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; DNA-binding; Nucleus; Phosphoprotein;
KW Polymorphism; Proto-oncogene; Reference proteome; Transcription;
KW Transcription regulation.
FT CHAIN 1 331 Transcription factor AP-1.
FT /FTId=PRO_0000076429.
FT DOMAIN 252 315 bZIP.
FT REGION 252 279 Basic motif (By similarity).
FT REGION 280 308 Leucine-zipper (By similarity).
FT SITE 272 272 Necessary for syngernistic
FT transcriptional activity with SMAD3.
FT MOD_RES 2 2 Phosphothreonine; by PAK2.
FT MOD_RES 8 8 Phosphothreonine; by PAK2.
FT MOD_RES 58 58 Phosphoserine.
FT MOD_RES 63 63 Phosphoserine; by MAPK8 and PLK3.
FT MOD_RES 73 73 Phosphoserine; by MAPK8 and PLK3.
FT MOD_RES 89 89 Phosphothreonine; by PAK2.
FT MOD_RES 93 93 Phosphothreonine; by PAK2.
FT MOD_RES 239 239 Phosphothreonine; by GSK3-beta.
FT MOD_RES 243 243 Phosphoserine; by DYRK2 and GSK3-beta.
FT MOD_RES 249 249 Phosphoserine; by GSK3-beta.
FT MOD_RES 271 271 N6-acetyllysine.
FT MOD_RES 286 286 Phosphothreonine; by PAK2.
FT VARIANT 297 297 T -> M (in dbSNP:rs9989).
FT /FTId=VAR_012070.
FT MUTAGEN 2 2 T->A: Complete loss of PAK2-mediated
FT phosphorylation; when associated with A-
FT 8; A-89; A-93; and A-286.
FT MUTAGEN 8 8 T->A: Complete loss of PAK2-mediated
FT phosphorylation; when associated with A-
FT 2; A-89; A-93; and A-286.
FT MUTAGEN 63 63 S->A: Greatly reduced ATF7-mediated
FT transcriptional activity; when associated
FT with A-73.
FT MUTAGEN 73 73 S->A: Greatly reduced ATF7-mediated
FT transcriptional activity; when associated
FT with A-63.
FT MUTAGEN 89 89 T->A: Complete loss of PAK2-mediated
FT phosphorylation; when associated with A-
FT 2; A-8; A-93; and A-286.
FT MUTAGEN 93 93 T->A: Complete loss of PAK2-mediated
FT phosphorylation; when associated with A-
FT 2; A-8; A-89; and A-286.
FT MUTAGEN 243 243 S->A: Abolishes phosphorylation by DYRK2.
FT Abolishes phosphorylation by GSK3B at
FT Thr-239.
FT MUTAGEN 272 272 R->V: Abolishes the syngernistic activity
FT with SMAD3 to activate TGF-beta-mediated
FT transcription.
FT MUTAGEN 286 286 T->A: Complete loss of PAK2-mediated
FT phosphorylation; when associated with A-
FT 2; A-8; A-89; and A-93.
FT CONFLICT 11 11 D -> G (in Ref. 2; AA sequence).
FT CONFLICT 14 14 L -> F (in Ref. 2; AA sequence).
FT CONFLICT 80 80 I -> V (in Ref. 2; AA sequence).
FT HELIX 255 306
SQ SEQUENCE 331 AA; 35676 MW; 0695E23AC4D33561 CRC64;
MTAKMETTFY DDALNASFLP SESGPYGYSN PKILKQSMTL NLADPVGSLK PHLRAKNSDL
LTSPDVGLLK LASPELERLI IQSSNGHITT TPTPTQFLCP KNVTDEQEGF AEGFVRALAE
LHSQNTLPSV TSAAQPVNGA GMVAPAVASV AGGSGSGGFS ASLHSEPPVY ANLSNFNPGA
LSSGGGAPSY GAAGLAFPAQ PQQQQQPPHH LPQQMPVQHP RLQALKEEPQ TVPEMPGETP
PLSPIDMESQ ERIKAERKRM RNRIAASKCR KRKLERIARL EEKVKTLKAQ NSELASTANM
LREQVAQLKQ KVMNHVNSGC QLMLTQQLQT F
//
ID JUN_HUMAN Reviewed; 331 AA.
AC P05412; Q96G93;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1989, sequence version 2.
DT 22-JAN-2014, entry version 184.
DE RecName: Full=Transcription factor AP-1;
DE AltName: Full=Activator protein 1;
DE Short=AP1;
DE AltName: Full=Proto-oncogene c-Jun;
DE AltName: Full=V-jun avian sarcoma virus 17 oncogene homolog;
DE AltName: Full=p39;
GN Name=JUN;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3194415; DOI=10.1073/pnas.85.23.9148;
RA Hattori K., Angel P., le Beau M.M., Karin M.;
RT "Structure and chromosomal localization of the functional intronless
RT human JUN protooncogene.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:9148-9152(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2825349; DOI=10.1126/science.2825349;
RA Bohmann D., Bos T.J., Admon A., Nishimura T., Vogt P.K., Tjian R.;
RT "Human proto-oncogene c-jun encodes a DNA binding protein with
RT structural and functional properties of transcription factor AP-1.";
RL Science 238:1386-1392(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=B-cell, Ovary, Testis, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PHOSPHORYLATION AT THR-239; SER-243 AND SER-249 BY GSK3B.
RX PubMed=1846781; DOI=10.1016/0092-8674(91)90241-P;
RA Boyle W.J., Smeal T., Defize L.H., Angel P., Woodgett J.R., Karin M.,
RA Hunter T.;
RT "Activation of protein kinase C decreases phosphorylation of c-Jun at
RT sites that negatively regulate its DNA-binding activity.";
RL Cell 64:573-584(1991).
RN [8]
RP PHOSPHORYLATION AT SER-249.
RX PubMed=8464713; DOI=10.1093/nar/21.5.1289;
RA Bannister A.J., Gottlieb T.M., Kouzarides T., Jackson S.P.;
RT "c-Jun is phosphorylated by the DNA-dependent protein kinase in vitro;
RT definition of the minimal kinase recognition motif.";
RL Nucleic Acids Res. 21:1289-1295(1993).
RN [9]
RP PHOSPHORYLATION BY CAMK4.
RX PubMed=8855261; DOI=10.1073/pnas.93.20.10803;
RA Enslen H., Tokumitsu H., Stork P.J., Davis R.J., Soderling T.R.;
RT "Regulation of mitogen-activated protein kinases by a
RT calcium/calmodulin-dependent protein kinase cascade.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:10803-10808(1996).
RN [10]
RP INTERACTION WITH TCF20.
RX PubMed=8663478; DOI=10.1074/jbc.271.30.18231;
RA Kirstein M., Sanz L., Moscat J., Diaz-Meco M.T., Saus J.;
RT "Cross-talk between different enhancer elements during mitogenic
RT induction of the human stromelysin-1 gene.";
RL J. Biol. Chem. 271:18231-18236(1996).
RN [11]
RP INTERACTION WITH COPS5.
RX PubMed=8837781; DOI=10.1038/383453a0;
RA Claret F.-X., Hibi M., Dhut S., Toda T., Karin M.;
RT "A new group of conserved coactivators that increase the specificity
RT of AP-1 transcription factors.";
RL Nature 383:453-457(1996).
RN [12]
RP IDENTIFICATION AS A COMPONENT OF THE SMAD3/SMAD4/JUN/FOS COMPLEX, AND
RP INTERACTION WITH SMAD3.
RX PubMed=9732876; DOI=10.1038/29814;
RA Zhang Y., Feng X.H., Derynck R.;
RT "Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-
RT induced transcription.";
RL Nature 394:909-913(1998).
RN [13]
RP INTERACTION WITH SPIB.
RX PubMed=10196196; DOI=10.1074/jbc.274.16.11115;
RA Rao S., Matsumura A., Yoon J., Simon M.C.;
RT "SPI-B activates transcription via a unique proline, serine, and
RT threonine domain and exhibits DNA binding affinity differences from
RT PU.1.";
RL J. Biol. Chem. 274:11115-11124(1999).
RN [14]
RP INTERACTION WITH ATF7, AND MUTAGENESIS OF SER-63 AND SER-73.
RX PubMed=10376527; DOI=10.1038/sj.onc.1202723;
RA De Graeve F., Bahr A., Sabapathy K.T., Hauss C., Wagner E.F.,
RA Kedinger C., Chatton B.;
RT "Role of the ATFa/JNK2 complex in Jun activation.";
RL Oncogene 18:3491-3500(1999).
RN [15]
RP INTERACTION WITH SMAD3 IN THE SMAD3/SMAD4/JUN/FOS COMPLEX,
RP DNA-BINDING, FUNCTION, AND MUTAGENESIS OF ARG-272.
RX PubMed=10995748; DOI=10.1074/jbc.M004731200;
RA Qing J., Zhang Y., Derynck R.;
RT "Structural and functional characterization of the transforming growth
RT factor-beta -induced Smad3/c-Jun transcriptional cooperativity.";
RL J. Biol. Chem. 275:38802-38812(2000).
RN [16]
RP ACETYLATION AT LYS-271 BY EP300.
RX PubMed=11689449; DOI=10.1093/emboj/20.21.6095;
RA Vries R.G., Prudenziati M., Zwartjes C., Verlaan M., Kalkhoven E.,
RA Zantema A.;
RT "A specific lysine in c-Jun is required for transcriptional repression
RT by E1A and is acetylated by p300.";
RL EMBO J. 20:6095-6103(2001).
RN [17]
RP INTERACTION WITH BATF3.
RX PubMed=12087103; DOI=10.1074/jbc.M205048200;
RA Bower K.E., Zeller R.W., Wachsman W., Martinez T., McGuire K.L.;
RT "Correlation of transcriptional repression by p21(SNFT) with changes
RT in DNA.NF-AT complex interactions.";
RL J. Biol. Chem. 277:34967-34977(2002).
RN [18]
RP INTERACTION WITH BATF3.
RX PubMed=15467742; DOI=10.1038/sj.onc.1208109;
RA Bower K.E., Fritz J.M., McGuire K.L.;
RT "Transcriptional repression of MMP-1 by p21SNFT and reduced in vitro
RT invasiveness of hepatocarcinoma cells.";
RL Oncogene 23:8805-8814(2004).
RN [19]
RP FUNCTION, AND PHOSPHORYLATION BY HIPK3.
RX PubMed=17210646; DOI=10.1128/MCB.02253-06;
RA Lan H.-C., Li H.-J., Lin G., Lai P.-Y., Chung B.-C.;
RT "Cyclic AMP stimulates SF-1-dependent CYP11A1 expression through
RT homeodomain-interacting protein kinase 3-mediated Jun N-terminal
RT kinase and c-Jun phosphorylation.";
RL Mol. Cell. Biol. 27:2027-2036(2007).
RN [20]
RP INTERACTION WITH SP1.
RX PubMed=16478997; DOI=10.1128/MCB.26.5.1770-1785.2006;
RA Hung J.J., Wang Y.T., Chang W.C.;
RT "Sp1 deacetylation induced by phorbol ester recruits p300 to activate
RT 12(S)-lipoxygenase gene transcription.";
RL Mol. Cell. Biol. 26:1770-1785(2006).
RN [21]
RP PHOSPHORYLATION AT SER-63 AND SER-73.
RX PubMed=17804415; DOI=10.1074/jbc.M702791200;
RA Wang L., Dai W., Lu L.;
RT "Stress-induced c-Jun activation mediated by Polo-like kinase 3 in
RT corneal epithelial cells.";
RL J. Biol. Chem. 282:32121-32127(2007).
RN [22]
RP PHOSPHORYLATION AT SER-63 AND SER-73.
RX PubMed=18650425; DOI=10.1074/jbc.M801326200;
RA Wang L., Gao J., Dai W., Lu L.;
RT "Activation of Polo-like kinase 3 by hypoxic stresses.";
RL J. Biol. Chem. 283:25928-25935(2008).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-58; SER-63; THR-239 AND
RP SER-243, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-63 AND SER-243, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [26]
RP INTERACTION WITH RNF187.
RX PubMed=20852630; DOI=10.1038/ncb2098;
RA Davies C.C., Chakraborty A., Cipriani F., Haigh K., Haigh J.J.,
RA Behrens A.;
RT "Identification of a co-activator that links growth factor signalling
RT to c-Jun/AP-1 activation.";
RL Nat. Cell Biol. 12:963-972(2010).
RN [27]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-63, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [28]
RP PHOSPHORYLATION AT THR-2; THR-8; THR-89; THR-93 AND THR-286, AND
RP MUTAGENESIS OF THR-2; THR-8; THR-89; THR-93 AND THR-286.
RX PubMed=21177766; DOI=10.1093/carcin/bgq271;
RA Li T., Zhang J., Zhu F., Wen W., Zykova T., Li X., Liu K., Peng C.,
RA Ma W., Shi G., Dong Z., Bode A.M., Dong Z.;
RT "P21-activated protein kinase (PAK2)-mediated c-Jun phosphorylation at
RT 5 threonine sites promotes cell transformation.";
RL Carcinogenesis 32:659-666(2011).
RN [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-58 AND SER-63, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [30]
RP PHOSPHORYLATION AT SER-243, AND MUTAGENESIS OF SER-243.
RX PubMed=22307329; DOI=10.1172/JCI60818;
RA Taira N., Mimoto R., Kurata M., Yamaguchi T., Kitagawa M., Miki Y.,
RA Yoshida K.;
RT "DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle
RT progression in human cancer cells.";
RL J. Clin. Invest. 122:859-872(2012).
RN [31]
RP INTERACTION WITH RNF187.
RX PubMed=23624934; DOI=10.1038/emboj.2013.98;
RA Davies C.C., Chakraborty A., Diefenbacher M.E., Skehel M., Behrens A.;
RT "Arginine methylation of the c-Jun coactivator RACO-1 is required for
RT c-Jun/AP-1 activation.";
RL EMBO J. 32:1556-1567(2013).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (3.05 ANGSTROMS) OF 257-313 OF COMPLEX WITH FOS.
RX PubMed=7816143; DOI=10.1038/373257a0;
RA Glover J.N., Harrison S.C.;
RT "Crystal structure of the heterodimeric bZIP transcription factor c-
RT Fos-c-Jun bound to DNA.";
RL Nature 373:257-261(1995).
RN [33]
RP STRUCTURE BY NMR OF 276-314.
RX PubMed=8662824; DOI=10.1074/jbc.271.23.13663;
RA Junius F.K., O'Donoghue S.I., Nilges M., Weiss A.S., King G.F.;
RT "High resolution NMR solution structure of the leucine zipper domain
RT of the c-Jun homodimer.";
RL J. Biol. Chem. 271:13663-13667(1996).
CC -!- FUNCTION: Transcription factor that recognizes and binds to the
CC enhancer heptamer motif 5'-TGA[CG]TCA-3'. Promotes activity of
CC NR5A1 when phosphorylated by HIPK3 leading to increased
CC steroidogenic gene expression upon cAMP signaling pathway
CC stimulation.
CC -!- SUBUNIT: Heterodimer with either FOS or BATF3 or ATF7. The
CC ATF7/JUN heterodimer is essential for ATF7 transactivation
CC activity. Interacts with DSIPI; the interaction inhibits the
CC binding of active AP1 to its target DNA (By similarity). Interacts
CC with HIVEP3 and MYBBP1A (By similarity). Interacts with SP1, SPIB
CC and TCF20. Interacts with COPS5; the interaction leads indirectly
CC to its phosphorylation. Component of the
CC SMAD3/SMAD4/JUN/FOS/complex which forms at the AP1 promoter site.
CC The SMAD3/SMAD4 heterodimer acts syngernistically with the JUN/FOS
CC heterodimer to activate transcription in response to TGF-beta.
CC Interacts (via its basic DNA binding and leucine zipper domains)
CC with SMAD3 (via an N-terminal domain); the interaction is required
CC for TGF-beta-mediated transactivation of the
CC SMAD3/SMAD4/JUN/FOS/complex. Interacts with methylated RNF187.
CC Binds to HIPK3.
CC -!- INTERACTION:
CC Q06481:APLP2; NbExp=3; IntAct=EBI-852823, EBI-79306;
CC P05067:APP; NbExp=2; IntAct=EBI-852823, EBI-77613;
CC P15336:ATF2; NbExp=5; IntAct=EBI-852823, EBI-1170906;
CC Q8IWZ6:BBS7; NbExp=3; IntAct=EBI-852823, EBI-1806001;
CC Q99966:CITED1; NbExp=2; IntAct=EBI-852823, EBI-2624951;
CC O43889:CREB3; NbExp=4; IntAct=EBI-852823, EBI-625002;
CC P14921:ETS1; NbExp=3; IntAct=EBI-852823, EBI-913209;
CC P01100:FOS; NbExp=21; IntAct=EBI-852823, EBI-852851;
CC P07900:HSP90AA1; NbExp=2; IntAct=EBI-852823, EBI-296047;
CC Q8WQG9:jnk-1 (xeno); NbExp=3; IntAct=EBI-852823, EBI-321822;
CC P52292:KPNA2; NbExp=2; IntAct=EBI-852823, EBI-349938;
CC P53779:MAPK10; NbExp=2; IntAct=EBI-852823, EBI-713543;
CC P45983:MAPK8; NbExp=4; IntAct=EBI-852823, EBI-286483;
CC P45983-1:MAPK8; NbExp=2; IntAct=EBI-852823, EBI-288687;
CC Q9UPY8:MAPRE3; NbExp=3; IntAct=EBI-852823, EBI-726739;
CC Q00987:MDM2; NbExp=3; IntAct=EBI-852823, EBI-389668;
CC P48634:PRRC2A; NbExp=2; IntAct=EBI-852823, EBI-347545;
CC Q9NRL3:STRN4; NbExp=3; IntAct=EBI-852823, EBI-717245;
CC Q99986:VRK1; NbExp=4; IntAct=EBI-852823, EBI-1769146;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- PTM: Phosphorylated by CaMK4 and PRKDC; phosphorylation enhances
CC the transcriptional activity. Phosphorylated by HIPK3.
CC Phosphorylated by DYRK2 at Ser-243; this primes the protein for
CC subsequent phosphorylation by GSK3B at Thr-239. Phosphorylated at
CC Thr-239, Ser-243 and Ser-249 by GSK3B; phosphorylation reduces its
CC ability to bind DNA. Phosphorylated by PAK2 at Thr-2, Thr-8, Thr-
CC 89, Thr-93 and Thr-286 thereby promoting JUN-mediated cell
CC proliferation and transformation. Phosphorylated by PLK3 following
CC hypoxia or UV irradiation, leading to increase DNA-binding
CC activity.
CC -!- PTM: Acetylated at Lys-271 by EP300.
CC -!- SIMILARITY: Belongs to the bZIP family. Jun subfamily.
CC -!- SIMILARITY: Contains 1 bZIP (basic-leucine zipper) domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/JUNID151.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/jun/";
CC -----------------------------------------------------------------------
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DR EMBL; J04111; AAA59197.1; -; Genomic_DNA.
DR EMBL; BT019759; AAV38564.1; -; mRNA.
DR EMBL; AY217548; AAO22993.1; -; Genomic_DNA.
DR EMBL; AL136985; CAC10201.1; -; Genomic_DNA.
DR EMBL; BC002646; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC006175; AAH06175.1; -; mRNA.
DR EMBL; BC009874; AAH09874.2; -; mRNA.
DR EMBL; BC068522; AAH68522.1; -; mRNA.
DR PIR; A31264; TVHUJN.
DR RefSeq; NP_002219.1; NM_002228.3.
DR UniGene; Hs.696684; -.
DR PDB; 1A02; X-ray; 2.70 A; J=254-308.
DR PDB; 1FOS; X-ray; 3.05 A; F/H=254-315.
DR PDB; 1JNM; X-ray; 2.20 A; A/B=254-315.
DR PDB; 1JUN; NMR; -; A/B=276-314.
DR PDB; 1S9K; X-ray; 3.10 A; E=257-308.
DR PDB; 1T2K; X-ray; 3.00 A; C=254-314.
DR PDBsum; 1A02; -.
DR PDBsum; 1FOS; -.
DR PDBsum; 1JNM; -.
DR PDBsum; 1JUN; -.
DR PDBsum; 1S9K; -.
DR PDBsum; 1T2K; -.
DR ProteinModelPortal; P05412; -.
DR SMR; P05412; 257-308.
DR DIP; DIP-5961N; -.
DR IntAct; P05412; 61.
DR MINT; MINT-105756; -.
DR STRING; 9606.ENSP00000360266; -.
DR BindingDB; P05412; -.
DR ChEMBL; CHEMBL2111421; -.
DR DrugBank; DB01169; Arsenic trioxide.
DR DrugBank; DB01029; Irbesartan.
DR DrugBank; DB00570; Vinblastine.
DR PhosphoSite; P05412; -.
DR DMDM; 135298; -.
DR PaxDb; P05412; -.
DR PRIDE; P05412; -.
DR DNASU; 3725; -.
DR Ensembl; ENST00000371222; ENSP00000360266; ENSG00000177606.
DR GeneID; 3725; -.
DR KEGG; hsa:3725; -.
DR UCSC; uc001cze.3; human.
DR CTD; 3725; -.
DR GeneCards; GC01M059246; -.
DR H-InvDB; HIX0000635; -.
DR HGNC; HGNC:6204; JUN.
DR HPA; CAB003801; -.
DR HPA; CAB007780; -.
DR MIM; 165160; gene.
DR neXtProt; NX_P05412; -.
DR PharmGKB; PA30006; -.
DR eggNOG; NOG283376; -.
DR HOGENOM; HOG000006648; -.
DR HOVERGEN; HBG001722; -.
DR InParanoid; P05412; -.
DR KO; K04448; -.
DR OMA; KPHLRNK; -.
DR OrthoDB; EOG75MVXV; -.
DR PhylomeDB; P05412; -.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P05412; -.
DR ChiTaRS; Jun; human.
DR EvolutionaryTrace; P05412; -.
DR GeneWiki; C-jun; -.
DR GenomeRNAi; 3725; -.
DR NextBio; 14583; -.
DR PRO; PR:P05412; -.
DR Bgee; P05412; -.
DR CleanEx; HS_JUN; -.
DR Genevestigator; P05412; -.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005719; C:nuclear euchromatin; IDA:BHF-UCL.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005667; C:transcription factor complex; IEA:Ensembl.
DR GO; GO:0017053; C:transcriptional repressor complex; IEA:Ensembl.
DR GO; GO:0035497; F:cAMP response element binding; IDA:BHF-UCL.
DR GO; GO:0003690; F:double-stranded DNA binding; IEA:Ensembl.
DR GO; GO:0005100; F:Rho GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0001077; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription; IEA:Ensembl.
DR GO; GO:0000980; F:RNA polymerase II distal enhancer sequence-specific DNA binding; IDA:BHF-UCL.
DR GO; GO:0003705; F:RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0001190; F:RNA polymerase II transcription factor binding transcription factor activity involved in positive regulation of transcription; IC:BHF-UCL.
DR GO; GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR GO; GO:0031103; P:axon regeneration; IEA:Ensembl.
DR GO; GO:0071277; P:cellular response to calcium ion; IEA:Ensembl.
DR GO; GO:0051365; P:cellular response to potassium ion starvation; IEA:Ensembl.
DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0035026; P:leading edge cell differentiation; IEA:Ensembl.
DR GO; GO:0007612; P:learning; IEA:Ensembl.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0051899; P:membrane depolarization; IEA:Ensembl.
DR GO; GO:0001774; P:microglial cell activation; IEA:Ensembl.
DR GO; GO:0030224; P:monocyte differentiation; IEA:Ensembl.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043922; P:negative regulation by host of viral transcription; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0043392; P:negative regulation of DNA binding; IDA:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0031953; P:negative regulation of protein autophosphorylation; IEA:Ensembl.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0003151; P:outflow tract morphogenesis; IEA:Ensembl.
DR GO; GO:0043923; P:positive regulation by host of viral transcription; IDA:UniProtKB.
DR GO; GO:0045740; P:positive regulation of DNA replication; IEA:Ensembl.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IEA:Ensembl.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IEA:Ensembl.
DR GO; GO:0045657; P:positive regulation of monocyte differentiation; IEA:Ensembl.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0051726; P:regulation of cell cycle; IEA:Ensembl.
DR GO; GO:0051090; P:regulation of sequence-specific DNA binding transcription factor activity; TAS:Reactome.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IEA:Ensembl.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0034097; P:response to cytokine stimulus; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0042542; P:response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0009314; P:response to radiation; IEA:Ensembl.
DR GO; GO:0007184; P:SMAD protein import into nucleus; IDA:BHF-UCL.
DR GO; GO:0060395; P:SMAD protein signal transduction; IDA:BHF-UCL.
DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.880.10; -; 1.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR015558; C_Jun.
DR InterPro; IPR005643; JNK.
DR InterPro; IPR002112; Leuzip_Jun.
DR InterPro; IPR008917; TF_DNA-bd.
DR PANTHER; PTHR11462:SF8; PTHR11462:SF8; 1.
DR Pfam; PF00170; bZIP_1; 1.
DR Pfam; PF03957; Jun; 1.
DR PRINTS; PR00043; LEUZIPPRJUN.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF47454; SSF47454; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; DNA-binding; Nucleus; Phosphoprotein;
KW Polymorphism; Proto-oncogene; Reference proteome; Transcription;
KW Transcription regulation.
FT CHAIN 1 331 Transcription factor AP-1.
FT /FTId=PRO_0000076429.
FT DOMAIN 252 315 bZIP.
FT REGION 252 279 Basic motif (By similarity).
FT REGION 280 308 Leucine-zipper (By similarity).
FT SITE 272 272 Necessary for syngernistic
FT transcriptional activity with SMAD3.
FT MOD_RES 2 2 Phosphothreonine; by PAK2.
FT MOD_RES 8 8 Phosphothreonine; by PAK2.
FT MOD_RES 58 58 Phosphoserine.
FT MOD_RES 63 63 Phosphoserine; by MAPK8 and PLK3.
FT MOD_RES 73 73 Phosphoserine; by MAPK8 and PLK3.
FT MOD_RES 89 89 Phosphothreonine; by PAK2.
FT MOD_RES 93 93 Phosphothreonine; by PAK2.
FT MOD_RES 239 239 Phosphothreonine; by GSK3-beta.
FT MOD_RES 243 243 Phosphoserine; by DYRK2 and GSK3-beta.
FT MOD_RES 249 249 Phosphoserine; by GSK3-beta.
FT MOD_RES 271 271 N6-acetyllysine.
FT MOD_RES 286 286 Phosphothreonine; by PAK2.
FT VARIANT 297 297 T -> M (in dbSNP:rs9989).
FT /FTId=VAR_012070.
FT MUTAGEN 2 2 T->A: Complete loss of PAK2-mediated
FT phosphorylation; when associated with A-
FT 8; A-89; A-93; and A-286.
FT MUTAGEN 8 8 T->A: Complete loss of PAK2-mediated
FT phosphorylation; when associated with A-
FT 2; A-89; A-93; and A-286.
FT MUTAGEN 63 63 S->A: Greatly reduced ATF7-mediated
FT transcriptional activity; when associated
FT with A-73.
FT MUTAGEN 73 73 S->A: Greatly reduced ATF7-mediated
FT transcriptional activity; when associated
FT with A-63.
FT MUTAGEN 89 89 T->A: Complete loss of PAK2-mediated
FT phosphorylation; when associated with A-
FT 2; A-8; A-93; and A-286.
FT MUTAGEN 93 93 T->A: Complete loss of PAK2-mediated
FT phosphorylation; when associated with A-
FT 2; A-8; A-89; and A-286.
FT MUTAGEN 243 243 S->A: Abolishes phosphorylation by DYRK2.
FT Abolishes phosphorylation by GSK3B at
FT Thr-239.
FT MUTAGEN 272 272 R->V: Abolishes the syngernistic activity
FT with SMAD3 to activate TGF-beta-mediated
FT transcription.
FT MUTAGEN 286 286 T->A: Complete loss of PAK2-mediated
FT phosphorylation; when associated with A-
FT 2; A-8; A-89; and A-93.
FT CONFLICT 11 11 D -> G (in Ref. 2; AA sequence).
FT CONFLICT 14 14 L -> F (in Ref. 2; AA sequence).
FT CONFLICT 80 80 I -> V (in Ref. 2; AA sequence).
FT HELIX 255 306
SQ SEQUENCE 331 AA; 35676 MW; 0695E23AC4D33561 CRC64;
MTAKMETTFY DDALNASFLP SESGPYGYSN PKILKQSMTL NLADPVGSLK PHLRAKNSDL
LTSPDVGLLK LASPELERLI IQSSNGHITT TPTPTQFLCP KNVTDEQEGF AEGFVRALAE
LHSQNTLPSV TSAAQPVNGA GMVAPAVASV AGGSGSGGFS ASLHSEPPVY ANLSNFNPGA
LSSGGGAPSY GAAGLAFPAQ PQQQQQPPHH LPQQMPVQHP RLQALKEEPQ TVPEMPGETP
PLSPIDMESQ ERIKAERKRM RNRIAASKCR KRKLERIARL EEKVKTLKAQ NSELASTANM
LREQVAQLKQ KVMNHVNSGC QLMLTQQLQT F
//
MIM
165160
*RECORD*
*FIELD* NO
165160
*FIELD* TI
*165160 V-JUN AVIAN SARCOMA VIRUS 17 ONCOGENE HOMOLOG; JUN
;;ONCOGENE JUN
ACTIVATOR PROTEIN 1, INCLUDED; AP1, INCLUDED;;
read moreENHANCER-BINDING PROTEIN AP1, INCLUDED
*FIELD* TX
DESCRIPTION
The oncogene JUN is the putative transforming gene of avian sarcoma
virus 17; it appears to be derived from a gene of the chicken genome and
has homologs in several other vertebrate species. (The name JUN comes
from the Japanese 'ju-nana,' meaning the number 17.) JUN was originally
thought to be identical to the transcription factor AP1. However, it is
now known that AP1 is not a single protein, but constitutes a group of
related dimeric basic region-leucine zipper proteins that belong to the
JUN, FOS (164810), MAF (177075), and ATF (see 603148) subfamilies. The
various dimers recognize either 12-O-tetradecanoylphorbol-13-acetate
(TPA) response elements or cAMP response elements. JUN is the most
potent transcriptional activator in its group, and its transcriptional
activity is attenuated and sometimes antagonized by JUNB (165161). For a
review of the structure and function of the AP1 transcription complexes,
see Shaulian and Karin (2002).
CLONING
Bohmann et al. (1987) isolated the human protooncogene JUN and found
that the deduced amino acid sequence is more than 80% identical to that
of the viral protein. Expression of cloned cDNA in bacteria produced a
protein with sequence-specific DNA-binding properties identical to the
phorbol ester-inducible enhancer-binding protein AP1. Antibodies raised
against 2 distinct peptides derived from JUN reacted specifically with
human AP1. In addition, partial amino acid sequence of purified AP1
revealed tryptic peptides in common with the JUN protein. Nucleotide
sequence analysis indicated that the COOH-terminus of JUN is similar to
the corresponding part of a yeast transcriptional activator.
Hattori et al. (1988) isolated a genomic clone of human JUN and
determined its primary structure and transcription pattern. Transfection
experiments showed that the cloned gene is functional, as it encodes a
trans-acting factor that stimulates transcription of an AP1-dependent
reporter gene.
GENE FUNCTION
Lamph et al. (1988) investigated regulation of murine c-jun gene
transcription and found that both serum and phorbol-ester TPA induced
c-jun gene expression.
Marx (1988) reviewed information indicating that the protein encoded by
the JUN gene acts directly to activate gene transcription in response to
cell stimulation; that the product of the FOS oncogene cooperates with
the JUN product in fostering gene transcription; that there is a
structural and functional similarity between JUN and GCN4, which induces
the activity of a large set of genes needed for amino acid synthesis in
yeast; that specifically both have a DNA-binding domain on the carboxyl
end essential for the activation of genes; that the JUN and FOS proteins
are held together in a complex by a leucine zipper; and that there are
other JUN genes in addition to the original one.
Shaulian et al. (2000) found that in mouse fibroblasts, Jun was
necessary for cell cycle reentry of ultraviolet (UV)-irradiated cells
but did not participate in the response to ionizing radiation. Cells
lacking Jun underwent prolonged cell cycle arrest but resisted
apoptosis, whereas cells that expressed Jun constitutively did not
arrest and undergo apoptosis. This function of Jun was exerted through
negative regulation of p53 (191170) association with the p21 (116899)
promoter. Cells lacking Jun exhibited prolonged p21 induction, whereas
constitutive Jun inhibited UV-mediated p21 induction.
Whitfield et al. (2001) noted that apoptosis induced in rat sympathetic
neurons by nerve growth factor (NGF; see 162030) withdrawal can be
blocked by inhibitors of RNA and protein synthesis. They presented
experimental evidence that activation of the JNK (see 601158)/JUN
pathway and increased expression of BIM (603827) are key events required
for cytochrome c release and apoptosis following NGF withdrawal.
Sphingosylphosphocholine (SPC) is a deacylated derivative of
sphingomyelin known to accumulate in Niemann-Pick disease type A
(257200). SPC is a potent mitogen that increases intracellular free
Ca(2+) and free arachidonate through pathways that are only partly
protein kinase C-dependent. Berger et al. (1995) showed that SPC
increases specific DNA-binding activity of transcription activator AP1
in electrophoretic mobility-shift assays.
Using a Drosophila model synapse, Sanyal et al. (2002) analyzed cellular
functions and regulation of the immediate-early transcription factor
AP1, a heterodimer of the basic leucine zipper proteins FOS and JUN.
They observed that AP1 positively regulates synaptic strength and
synapse number, thus showing a greater range of influence than CREB
(123810). Observations from genetic epistasis and RNA quantification
experiments indicate that AP1 acts upstream of CREB, regulates levels of
CREB mRNA, and functions at the top of the hierarchy of transcription
factors known to regulate long-term plasticity. A JUN-kinase signaling
module provided a CREB-independent route for neuronal AP1 activation;
thus, CREB regulation of AP1 expression may, in some neurons, constitute
a positive feedback loop rather than the primary step in AP1 activation.
Mathas et al. (2002) found AP1 constitutively activated, with robust JUN
and JUNB overexpression, in all cell lines derived from patients with
classical Hodgkin lymphoma (236000) and anaplastic large cell lymphoma
(ALCL), but not in other lymphoma types. AP1 supported proliferation of
Hodgkin cells, but suppressed apoptosis of ALCL cells. Mathas et al.
(2002) noted that, whereas JUN is upregulated by an autoregulatory
process, JUNB is under the control of nuclear factor kappa-B (NFKB;
164011). They found that AP1 and NFKB cooperate and stimulate expression
of the cell cycle regulator cyclin D2 (123833), the protooncogene MET
(164860), and the lymphocyte homing receptor CCR7 (600242), which are
all strongly expressed in primary Hodgkin/Reed-Sternberg (HRS) cells.
Wertz et al. (2004) reported that human DET1 (608727) promotes
ubiquitination and degradation of the protooncogenic transcription
factor c-Jun by assembling a multisubunit ubiquitin ligase containing
DNA damage-binding protein-1 (DDB1; 600045), cullin 4A (CUL4A; 603137),
regulator of cullins-1 (ROC1; 603814), and constitutively
photomorphogenic-1 (COP1; 608067). Ablation of any subunit by RNA
interference stabilized c-Jun and increased c-Jun-activated
transcription. Wertz et al. (2004) concluded that their findings
characterized a c-Jun ubiquitin ligase and define a specific function
for DET1 in mammalian cells.
JUN and N-terminal kinases (JNK) are essential for neuronal microtubule
assembly and apoptosis. Phosphorylation of the activating protein 1
(AP1) transcription factor c-Jun, at multiple sites within its
transactivation domain, is required for JNK-induced neurotoxicity.
Nateri et al. (2004) reported that in neurons the stability of c-Jun is
regulated by the E3 ligase SCF(Fbw7) (FBXW7; 606278), which
ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation.
Fbxw7 depletion resulted in accumulation of phosphorylated c-Jun,
stimulation of AP1 activity, and neuronal apoptosis. SCF-7 therefore
antagonizes the apoptotic c-Jun-dependent effector arm of JNK signaling,
allowing neurons to tolerate potentially neurotoxic JNK activity.
Fang and Kerppola (2004) found evidence that JUN proteins ubiquitinated
by ITCH (606409) are targeted to lysosomes for degradation. Mutation of
the ITCH recognition motif in the N terminus of JUN eliminated its
ubiquitination and increased its stability.
Ikeda et al. (2004) generated transgenic mice expressing
dominant-negative c-Jun specifically in the osteoclast lineage and found
that they developed severe osteopetrosis due to impaired
osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited
soluble RANKL (602642)-induced osteoclast differentiation in vitro.
Overexpression of nuclear factor of activated T cells 1 (NFATC2; 600490)
or NFATC1 (600489) promoted differentiation of osteoclast precursor
cells into tartrate-resistant acid phosphatase-positive (TRAP-positive)
multinucleated osteoclast-like cells even in the absence of RANKL. These
osteoclastogenic activities of NFAT were abrogated by overexpression of
dominant-negative c-Jun. Ikeda et al. (2004) concluded that c-Jun
signaling in cooperation with NFAT is crucial for RANKL-regulated
osteoclast differentiation.
Gao et al. (2004) found in the case of c-JUN and JUNB that extracellular
stimuli modulate protein turnover by regulating the activity of an E3
ligase by means of its phosphorylation. Activation of the Jun
amino-terminal kinase (JNK; see 601158) mitogen-activated protein kinase
(MAPK) cascade after T cell stimulation accelerated degradation of c-JUN
and JUNB through phosphorylation-dependent activation of the E3 ligase
ITCH. Gao et al. (2004) found that this pathway modulates cytokine
production by effector T cells.
Nateri et al. (2005) showed that phosphorylated c-JUN interacts with the
HMG-box transcription factor TCF4 (TCF7L2; 602228) to form a ternary
complex containing c-JUN, TCF4, and beta-catenin (see 116806). Chromatin
immunoprecipitation assays revealed JNK-dependent c-JUN-TCF4 interaction
on the c-JUN promoter, and c-JUN and TCF4 cooperatively activated the
c-JUN promoter in reporter assays in a beta-catenin-dependent manner. In
the Apc(Min) mouse model of intestinal cancer (see 611731), genetic
abrogation of c-JUN N-terminal phosphorylation or gut-specific
conditional c-JUN inactivation reduced tumor number and size and
prolonged life span. Therefore, Nateri et al. (2005) concluded that the
phosphorylation-dependent interaction between c-JUN and TCF4 regulates
intestinal tumorigenesis by integrating JNK and APC/beta-catenin, 2
distinct pathways activating WNT signaling.
Koyama-Nasu et al. (2007) showed that FBL10 (FBXL10; 609078) interacted
with JUN and repressed JUN-mediated transcription in human cell lines.
Chromatin immunoprecipitation assays demonstrated that FBL10 was present
at the JUN promoter and that JUN was required for recruitment of FBL10.
FBL10 bound unmethylated CpG sequences in the JUN promoter through its
CxxC zinc finger and tethered transcriptional repressor complexes.
Suppression of FBL10 expression by RNA interference induced
transcription of JUN and JUN target genes and caused aberrant cell cycle
progression and increased UV-induced cell death. Furthermore, FBL10
protein and mRNA were downregulated in response to UV in an inverse
correlation with JUN. Koyama-Nasu et al. (2007) concluded that FBL10 is
a key regulator of JUN function.
Aguilera et al. (2011) demonstrated that unphosphorylated, but not
N-terminally phosphorylated, c-Jun interacts with MBD3 (603573) and
thereby recruits the nucleosome remodeling and histone acetylation
(NuRD) repressor complex. MBD3 depletion in colon cancer cells increased
histone acetylation at AP1-dependent promoters, which resulted in
increased target gene expression. The intestinal stem cell marker LGR5
(606667) was identified as a novel target gene controlled by c-Jun/MBD3.
Gut-specific conditional deletion of Mbd3 in mice stimulated c-Jun
activity and increased progenitor cell proliferation. In response to
inflammation, Mbd3 deficiency resulted in colonic hyperproliferation,
and Mbd3 gut-null mice showed markedly increased susceptibility to
colitis-induced tumorigenesis. Aguilera et al. (2011) noted that
concomitant inactivation of a single allele of c-Jun reverted
physiologic and pathologic hyperproliferation, as well as the increased
tumorigenesis in Mbd3 gut-null mice. Thus, the transactivation domain of
c-Jun recruits MBD3/NuRD to AP1 target genes to mediate gene repression,
and this repression is relieved by JNK (601158)-mediated c-Jun
N-terminal phosphorylation.
Using chromatin immunoprecipitation sequencing in T-helper-17 (TH17)
cells, Glasmacher et al. (2012) found that IRF4 (601900) targets
sequences enriched for AP1-IRF composite elements (AICEs) that are
cobound by BATF (612476), an AP1 factor required for TH17, B, and
dendritic cell differentiation. IRF4 and BATF bind cooperatively to
structurally divergent AICEs to promote gene activation and TH17
differentiation. The AICE motif directs assembly of IRF4 or IRF8
(601565) with BATF heterodimers and is also used in TH2, B, and
dendritic cells. Glasmacher et al. (2012) concluded that this genomic
regulatory element and cognate factors appear to have evolved to
integrate diverse immunomodulatory signals.
GENE STRUCTURE
Hattori et al. (1988) determined that the JUN gene has no introns.
MAPPING
Haluska et al. (1988) isolated a genomic DNA clone encompassing the JUN
gene and used it to determine the chromosomal location. Southern blot
analysis of a rodent-human somatic cell hybrid panel indicated that JUN
is situated on 1p. In situ hybridization narrowed the assignment to
1p32-p31, a chromosomal region involved in both translocations and
deletions in human malignancies. By in situ hybridization, Hattori et
al. (1988) mapped JUN to 1p32-p31.
Mattei et al. (1990) mapped the mouse homolog to chromosome 4. Bahary et
al. (1991) presented molecular genetic linkage maps of mouse chromosome
4 which established the breakpoints in the mouse 4/human 1p region of
homology to a 2-cM interval between Ifa and Jun in mouse and to the
interval between JUN and ACADM (607008) in the human.
ANIMAL MODEL
Hilberg et al. (1993) developed Jun-null mice by gene targeting.
Heterozygous mutant mice appeared normal, but embryos lacking Jun died
between midgestation and late gestation and exhibited impaired
hepatogenesis, altered fetal liver erythropoiesis, and generalized
edema. Jun-defective embryonic stem cells were able to participate in
the development of all somatic cells in chimeric mice except liver
cells, indicating an essential function of Jun in hepatogenesis.
By alanine substitution of ser63 and ser73 of mouse Jun, Behrens et al.
(1999) demonstrated that phosphorylation on these residues was required
for several apoptotic functions. Mouse fibroblasts carrying mutated Jun
had proliferation- and stress-induced apoptotic defects accompanied by
reduced AP1 activity. Mutant mice were smaller than controls, and they
were resistant to epileptic seizures and neuronal apoptosis induced by
the excitotoxic amino acid kainate. Primary mutant neurons were also
protected from apoptosis.
Eferl et al. (2003) used liver-specific inactivation of Jun at different
stages of tumor development to study its role in chemically induced
hepatocellular carcinomas (HCCs) in mice. The requirement for Jun was
restricted to early stages of tumor development, and the number and size
of hepatic tumors was dramatically reduced when Jun was inactivated
after the tumor had initiated. The impaired tumor development correlated
with increased levels of p53 and its target gene Noxa (PMAIP1; 604959),
resulting in the induction of apoptosis without affecting cell
proliferation. Primary hepatocytes lacking Jun showed increased
sensitivity to tumor necrosis factor-alpha (TNF; 191160)-induced
apoptosis, which was abrogated in the absence of p53. These data
indicated that JUN prevents apoptosis by antagonizing p53 activity,
illustrating a mechanism that might contribute to the early stages of
human HCC development.
*FIELD* SA
Bos et al. (1988)
*FIELD* RF
1. Aguilera, C.; Nakagawa, K.; Sancho, R.; Chakraborty, A.; Hendrich,
B.; Behrens, A.: c-Jun N-terminal phosphorylation antagonises recruitment
of the Mbd3/NuRD repressor complex. Nature 469: 231-235, 2011.
2. Bahary, N.; Zorich, G.; Pachter, J. E.; Leibel, R. L.; Friedman,
J. M.: Molecular genetic linkage maps of mouse chromosomes 4 and
6. Genomics 11: 33-47, 1991.
3. Behrens, A.; Sibilia, M.; Wagner, E. F.: Amino-terminal phosphorylation
of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nature
Genet. 21: 326-329, 1999.
4. Berger, A.; Rosenthal, D.; Spiegel, S.: Sphingosylphosphocholine,
a signaling molecule which accumulates in Niemann-Pick disease type
A, stimulates DNA-binding activity of the transcription activator
protein AP-1. Proc. Nat. Acad. Sci. 92: 5885-5889, 1995.
5. Bohmann, D.; Bos, T. J.; Admon, A.; Nishimura, T.; Vogt, P. K.;
Tjian, R.: Human proto-oncogene c-jun encodes a DNA binding protein
with structural and functional properties of transcription factor
AP-1. Science 238: 1386-1392, 1987.
6. Bos, T. J.; Bohmann, D.; Tsuchie, H.; Tjian, R.; Vogt, P. K.:
v-jun encodes a nuclear protein with enhancer binding properties of
AP-1. Cell 52: 705-712, 1988.
7. Eferl, R.; Ricci, R.; Kenner, L.; Zenz, R.; David, J.-P.; Rath,
M.; Wagner, E. F.: Liver tumor development: c-Jun antagonizes the
proapoptotic activity of p53. Cell 112: 181-192, 2003.
8. Fang, D.; Kerppola, T. K.: Ubiquitin-mediated fluorescence complementation
reveals that Jun ubiquitinated by Itch/AIP4 is localized to lysosomes. Proc.
Nat. Acad. Sci. 101: 14782-14787, 2004.
9. Gao, M.; Labuda, T.; Xia, Y.; Gallagher, E.; Fang, D.; Liu, Y.-C.;
Karin, M.: Jun turnover is controlled through JNK-dependent phosphorylation
of the E3 ligase Itch. Science 306: 271-275, 2004.
10. Glasmacher, E.; Agrawal, S.; Chang, A. B.; Murphy, T. L.; Zeng,
W.; Vander Lugt, B.; Khan, A. A.; Ciofani, M.; Spooner, C. J.; Rutz,
S.; Hackney, J.; Nurieva, R.; Escalante, C. R.; Ouyang, W.; Littman,
D. R.; Murphy, K. M.; Singh, H.: A genomic regulatory element that
directs assembly and function of immune-specific AP-1-IRF complexes. Science 338:
975-980, 2012.
11. Haluska, F. G.; Huebner, K.; Isobe, M.; Nishimura, T.; Croce,
C. M.; Vogt, P. K.: Localization of the human JUN protooncogene to
chromosome region 1p31-32. Proc. Nat. Acad. Sci. 85: 2215-2218,
1988.
12. Hattori, K.; Angel, P.; Le Beau, M. M.; Karin, M.: Structure
and chromosomal localization of the functional intronless human JUN
protooncogene. Proc. Nat. Acad. Sci. 85: 9148-9152, 1988.
13. Hilberg, F.; Aguzzi, A.; Howells, N.; Wagner, E. F.: c-Jun is
essential for normal mouse development and hepatogenesis. Nature 365:
179-181, 1993. Note: Erratum: Nature 366: 368 only, 1993.
14. Ikeda, F.; Nishimura, R.; Matsubara, T.; Tanaka, S.; Ioune, J.;
Reddy, S. V.; Hata, K.; Yamashita, K.; Hiraga, T.; Watanabe, T.; Kukita,
T.; Yoshioka, K.; Rao, A.; Yoneda, T.: Critical roles of c-Jun signaling
in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J.
Clin. Invest. 114: 475-484, 2004.
15. Koyama-Nasu, R.; David, G.; Tanese, N.: The F-box protein Fbl10
is a novel transcriptional repressor of c-Jun. Nature Cell Biol. 9:
1074-1080, 2007.
16. Lamph, W. W.; Wamsley, P.; Sassone-Corsi, P.; Verma, I. M.: Induction
of proto-oncogene JUN/AP-1 by serum and TPA. Nature 334: 629-631,
1988.
17. Marx, J. L.: 'Jun' is bustin' out all over. (Research News). Science 242:
1377-1378, 1988.
18. Mathas, S.; Hinz, M.; Anagnostopoulos, I.; Krappmann, D.; Lietz,
A.; Jundt, F.; Bommert, K.; Mechta-Grigoriou, F.; Stein, H.; Dorken,
B.; Scheidereit, C.: Aberrantly expressed c-Jun and JunB are a hallmark
of Hodgkin lymphoma cells, stimulate proliferation and synergize with
NF-kappa-B. EMBO J. 21: 4104-4113, 2002.
19. Mattei, M. G.; Simon-Chazottes, D.; Hirai, S.-I.; Ryseck, R.-P.;
Galcheva-Gargova, Z.; Guenet, J. L.; Mattei, J. F.; Bravo, R.; Yaniv,
M.: Chromosomal localization of the three members of the jun proto-oncogene
family in mouse and man. Oncogene 5: 151-156, 1990.
20. Nateri, A. S.; Riera-Sans, L.; Da Costa, C.; Behrens, A.: The
ubiquitin ligase SCF(Fbw7) antagonizes apoptotic JNK signaling. Science 303:
1374-1378, 2004.
21. Nateri, A. S.; Spencer-Dene, B.; Behrens, A.: Interaction of
phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature 437:
281-285, 2005.
22. Sanyal, S.; Sandstrom, D. J.; Hoeffer, C. A.; Ramaswami, M.:
AP-1 function upstream of CREB to control synaptic plasticity in Drosophila. Nature 416:
870-874, 2002.
23. Shaulian, E.; Karin, M.: AP-1 as a regulator of cell life and
death. Nature Cell Biol. 4: E131-E136, 2002.
24. Shaulian, E.; Schreiber, M.; Piu, F.; Beeche, M.; Wagner, E. F.;
Karin, M.: The mammalian UV response: c-Jun induction is required
for exit from p53-imposed growth arrest. Cell 103: 897-907, 2000.
25. Wertz, I. E.; O'Rourke, K. M.; Zhang, Z.; Dornan, D.; Arnott,
D.; Deshaies, R. J.; Dixit, V. M.: Human de-etiolated-1 regulates
c-Jun by assembling a CUL4A ubiquitin ligase. Science 303: 1371-1374,
2004.
26. Whitfield, J.; Neame, S. J.; Paquet, L.; Bernard, O.; Ham, J.
: Dominant-negative c-Jun promotes neuronal survival by reducing BIM
expression and inhibiting mitochondrial cytochrome c release. Neuron 29:
629-643, 2001.
*FIELD* CN
Ada Hamosh - updated: 1/7/2013
Ada Hamosh - updated: 1/28/2011
Patricia A. Hartz - updated: 4/30/2008
Ada Hamosh - updated: 6/29/2007
Ada Hamosh - updated: 2/23/2005
Marla J. F. O'Neill - updated: 1/6/2005
Patricia A. Hartz - updated: 11/22/2004
Ada Hamosh - updated: 6/10/2004
Patricia A. Hartz - updated: 7/8/2003
Patricia A. Hartz - updated: 3/25/2003
Stylianos E. Antonarakis - updated: 2/4/2003
Patricia A. Hartz - updated: 10/30/2002
Patricia A. Hartz - updated: 10/4/2002
Ada Hamosh - updated: 5/8/2002
Stylianos E. Antonarakis - updated: 12/18/2000
*FIELD* CD
Victor A. McKusick: 12/23/1987
*FIELD* ED
terry: 04/04/2013
alopez: 1/7/2013
terry: 1/7/2013
alopez: 2/4/2011
terry: 1/28/2011
mgross: 4/30/2008
wwang: 2/27/2008
ckniffin: 2/5/2008
mgross: 11/14/2007
alopez: 7/2/2007
terry: 6/29/2007
terry: 3/16/2005
alopez: 2/23/2005
carol: 1/7/2005
terry: 1/6/2005
mgross: 11/22/2004
alopez: 6/11/2004
terry: 6/10/2004
mgross: 7/8/2003
mgross: 3/25/2003
mgross: 2/4/2003
mgross: 10/30/2002
mgross: 10/4/2002
carol: 6/20/2002
terry: 6/19/2002
ckniffin: 6/13/2002
alopez: 5/9/2002
terry: 5/8/2002
terry: 12/7/2001
mgross: 12/18/2000
alopez: 11/4/1998
alopez: 10/22/1998
mark: 3/26/1996
mark: 2/15/1996
mark: 7/24/1995
jason: 6/17/1994
supermim: 3/16/1992
carol: 9/6/1991
carol: 10/3/1990
carol: 9/13/1990
*RECORD*
*FIELD* NO
165160
*FIELD* TI
*165160 V-JUN AVIAN SARCOMA VIRUS 17 ONCOGENE HOMOLOG; JUN
;;ONCOGENE JUN
ACTIVATOR PROTEIN 1, INCLUDED; AP1, INCLUDED;;
read moreENHANCER-BINDING PROTEIN AP1, INCLUDED
*FIELD* TX
DESCRIPTION
The oncogene JUN is the putative transforming gene of avian sarcoma
virus 17; it appears to be derived from a gene of the chicken genome and
has homologs in several other vertebrate species. (The name JUN comes
from the Japanese 'ju-nana,' meaning the number 17.) JUN was originally
thought to be identical to the transcription factor AP1. However, it is
now known that AP1 is not a single protein, but constitutes a group of
related dimeric basic region-leucine zipper proteins that belong to the
JUN, FOS (164810), MAF (177075), and ATF (see 603148) subfamilies. The
various dimers recognize either 12-O-tetradecanoylphorbol-13-acetate
(TPA) response elements or cAMP response elements. JUN is the most
potent transcriptional activator in its group, and its transcriptional
activity is attenuated and sometimes antagonized by JUNB (165161). For a
review of the structure and function of the AP1 transcription complexes,
see Shaulian and Karin (2002).
CLONING
Bohmann et al. (1987) isolated the human protooncogene JUN and found
that the deduced amino acid sequence is more than 80% identical to that
of the viral protein. Expression of cloned cDNA in bacteria produced a
protein with sequence-specific DNA-binding properties identical to the
phorbol ester-inducible enhancer-binding protein AP1. Antibodies raised
against 2 distinct peptides derived from JUN reacted specifically with
human AP1. In addition, partial amino acid sequence of purified AP1
revealed tryptic peptides in common with the JUN protein. Nucleotide
sequence analysis indicated that the COOH-terminus of JUN is similar to
the corresponding part of a yeast transcriptional activator.
Hattori et al. (1988) isolated a genomic clone of human JUN and
determined its primary structure and transcription pattern. Transfection
experiments showed that the cloned gene is functional, as it encodes a
trans-acting factor that stimulates transcription of an AP1-dependent
reporter gene.
GENE FUNCTION
Lamph et al. (1988) investigated regulation of murine c-jun gene
transcription and found that both serum and phorbol-ester TPA induced
c-jun gene expression.
Marx (1988) reviewed information indicating that the protein encoded by
the JUN gene acts directly to activate gene transcription in response to
cell stimulation; that the product of the FOS oncogene cooperates with
the JUN product in fostering gene transcription; that there is a
structural and functional similarity between JUN and GCN4, which induces
the activity of a large set of genes needed for amino acid synthesis in
yeast; that specifically both have a DNA-binding domain on the carboxyl
end essential for the activation of genes; that the JUN and FOS proteins
are held together in a complex by a leucine zipper; and that there are
other JUN genes in addition to the original one.
Shaulian et al. (2000) found that in mouse fibroblasts, Jun was
necessary for cell cycle reentry of ultraviolet (UV)-irradiated cells
but did not participate in the response to ionizing radiation. Cells
lacking Jun underwent prolonged cell cycle arrest but resisted
apoptosis, whereas cells that expressed Jun constitutively did not
arrest and undergo apoptosis. This function of Jun was exerted through
negative regulation of p53 (191170) association with the p21 (116899)
promoter. Cells lacking Jun exhibited prolonged p21 induction, whereas
constitutive Jun inhibited UV-mediated p21 induction.
Whitfield et al. (2001) noted that apoptosis induced in rat sympathetic
neurons by nerve growth factor (NGF; see 162030) withdrawal can be
blocked by inhibitors of RNA and protein synthesis. They presented
experimental evidence that activation of the JNK (see 601158)/JUN
pathway and increased expression of BIM (603827) are key events required
for cytochrome c release and apoptosis following NGF withdrawal.
Sphingosylphosphocholine (SPC) is a deacylated derivative of
sphingomyelin known to accumulate in Niemann-Pick disease type A
(257200). SPC is a potent mitogen that increases intracellular free
Ca(2+) and free arachidonate through pathways that are only partly
protein kinase C-dependent. Berger et al. (1995) showed that SPC
increases specific DNA-binding activity of transcription activator AP1
in electrophoretic mobility-shift assays.
Using a Drosophila model synapse, Sanyal et al. (2002) analyzed cellular
functions and regulation of the immediate-early transcription factor
AP1, a heterodimer of the basic leucine zipper proteins FOS and JUN.
They observed that AP1 positively regulates synaptic strength and
synapse number, thus showing a greater range of influence than CREB
(123810). Observations from genetic epistasis and RNA quantification
experiments indicate that AP1 acts upstream of CREB, regulates levels of
CREB mRNA, and functions at the top of the hierarchy of transcription
factors known to regulate long-term plasticity. A JUN-kinase signaling
module provided a CREB-independent route for neuronal AP1 activation;
thus, CREB regulation of AP1 expression may, in some neurons, constitute
a positive feedback loop rather than the primary step in AP1 activation.
Mathas et al. (2002) found AP1 constitutively activated, with robust JUN
and JUNB overexpression, in all cell lines derived from patients with
classical Hodgkin lymphoma (236000) and anaplastic large cell lymphoma
(ALCL), but not in other lymphoma types. AP1 supported proliferation of
Hodgkin cells, but suppressed apoptosis of ALCL cells. Mathas et al.
(2002) noted that, whereas JUN is upregulated by an autoregulatory
process, JUNB is under the control of nuclear factor kappa-B (NFKB;
164011). They found that AP1 and NFKB cooperate and stimulate expression
of the cell cycle regulator cyclin D2 (123833), the protooncogene MET
(164860), and the lymphocyte homing receptor CCR7 (600242), which are
all strongly expressed in primary Hodgkin/Reed-Sternberg (HRS) cells.
Wertz et al. (2004) reported that human DET1 (608727) promotes
ubiquitination and degradation of the protooncogenic transcription
factor c-Jun by assembling a multisubunit ubiquitin ligase containing
DNA damage-binding protein-1 (DDB1; 600045), cullin 4A (CUL4A; 603137),
regulator of cullins-1 (ROC1; 603814), and constitutively
photomorphogenic-1 (COP1; 608067). Ablation of any subunit by RNA
interference stabilized c-Jun and increased c-Jun-activated
transcription. Wertz et al. (2004) concluded that their findings
characterized a c-Jun ubiquitin ligase and define a specific function
for DET1 in mammalian cells.
JUN and N-terminal kinases (JNK) are essential for neuronal microtubule
assembly and apoptosis. Phosphorylation of the activating protein 1
(AP1) transcription factor c-Jun, at multiple sites within its
transactivation domain, is required for JNK-induced neurotoxicity.
Nateri et al. (2004) reported that in neurons the stability of c-Jun is
regulated by the E3 ligase SCF(Fbw7) (FBXW7; 606278), which
ubiquitinates phosphorylated c-Jun and facilitates c-Jun degradation.
Fbxw7 depletion resulted in accumulation of phosphorylated c-Jun,
stimulation of AP1 activity, and neuronal apoptosis. SCF-7 therefore
antagonizes the apoptotic c-Jun-dependent effector arm of JNK signaling,
allowing neurons to tolerate potentially neurotoxic JNK activity.
Fang and Kerppola (2004) found evidence that JUN proteins ubiquitinated
by ITCH (606409) are targeted to lysosomes for degradation. Mutation of
the ITCH recognition motif in the N terminus of JUN eliminated its
ubiquitination and increased its stability.
Ikeda et al. (2004) generated transgenic mice expressing
dominant-negative c-Jun specifically in the osteoclast lineage and found
that they developed severe osteopetrosis due to impaired
osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited
soluble RANKL (602642)-induced osteoclast differentiation in vitro.
Overexpression of nuclear factor of activated T cells 1 (NFATC2; 600490)
or NFATC1 (600489) promoted differentiation of osteoclast precursor
cells into tartrate-resistant acid phosphatase-positive (TRAP-positive)
multinucleated osteoclast-like cells even in the absence of RANKL. These
osteoclastogenic activities of NFAT were abrogated by overexpression of
dominant-negative c-Jun. Ikeda et al. (2004) concluded that c-Jun
signaling in cooperation with NFAT is crucial for RANKL-regulated
osteoclast differentiation.
Gao et al. (2004) found in the case of c-JUN and JUNB that extracellular
stimuli modulate protein turnover by regulating the activity of an E3
ligase by means of its phosphorylation. Activation of the Jun
amino-terminal kinase (JNK; see 601158) mitogen-activated protein kinase
(MAPK) cascade after T cell stimulation accelerated degradation of c-JUN
and JUNB through phosphorylation-dependent activation of the E3 ligase
ITCH. Gao et al. (2004) found that this pathway modulates cytokine
production by effector T cells.
Nateri et al. (2005) showed that phosphorylated c-JUN interacts with the
HMG-box transcription factor TCF4 (TCF7L2; 602228) to form a ternary
complex containing c-JUN, TCF4, and beta-catenin (see 116806). Chromatin
immunoprecipitation assays revealed JNK-dependent c-JUN-TCF4 interaction
on the c-JUN promoter, and c-JUN and TCF4 cooperatively activated the
c-JUN promoter in reporter assays in a beta-catenin-dependent manner. In
the Apc(Min) mouse model of intestinal cancer (see 611731), genetic
abrogation of c-JUN N-terminal phosphorylation or gut-specific
conditional c-JUN inactivation reduced tumor number and size and
prolonged life span. Therefore, Nateri et al. (2005) concluded that the
phosphorylation-dependent interaction between c-JUN and TCF4 regulates
intestinal tumorigenesis by integrating JNK and APC/beta-catenin, 2
distinct pathways activating WNT signaling.
Koyama-Nasu et al. (2007) showed that FBL10 (FBXL10; 609078) interacted
with JUN and repressed JUN-mediated transcription in human cell lines.
Chromatin immunoprecipitation assays demonstrated that FBL10 was present
at the JUN promoter and that JUN was required for recruitment of FBL10.
FBL10 bound unmethylated CpG sequences in the JUN promoter through its
CxxC zinc finger and tethered transcriptional repressor complexes.
Suppression of FBL10 expression by RNA interference induced
transcription of JUN and JUN target genes and caused aberrant cell cycle
progression and increased UV-induced cell death. Furthermore, FBL10
protein and mRNA were downregulated in response to UV in an inverse
correlation with JUN. Koyama-Nasu et al. (2007) concluded that FBL10 is
a key regulator of JUN function.
Aguilera et al. (2011) demonstrated that unphosphorylated, but not
N-terminally phosphorylated, c-Jun interacts with MBD3 (603573) and
thereby recruits the nucleosome remodeling and histone acetylation
(NuRD) repressor complex. MBD3 depletion in colon cancer cells increased
histone acetylation at AP1-dependent promoters, which resulted in
increased target gene expression. The intestinal stem cell marker LGR5
(606667) was identified as a novel target gene controlled by c-Jun/MBD3.
Gut-specific conditional deletion of Mbd3 in mice stimulated c-Jun
activity and increased progenitor cell proliferation. In response to
inflammation, Mbd3 deficiency resulted in colonic hyperproliferation,
and Mbd3 gut-null mice showed markedly increased susceptibility to
colitis-induced tumorigenesis. Aguilera et al. (2011) noted that
concomitant inactivation of a single allele of c-Jun reverted
physiologic and pathologic hyperproliferation, as well as the increased
tumorigenesis in Mbd3 gut-null mice. Thus, the transactivation domain of
c-Jun recruits MBD3/NuRD to AP1 target genes to mediate gene repression,
and this repression is relieved by JNK (601158)-mediated c-Jun
N-terminal phosphorylation.
Using chromatin immunoprecipitation sequencing in T-helper-17 (TH17)
cells, Glasmacher et al. (2012) found that IRF4 (601900) targets
sequences enriched for AP1-IRF composite elements (AICEs) that are
cobound by BATF (612476), an AP1 factor required for TH17, B, and
dendritic cell differentiation. IRF4 and BATF bind cooperatively to
structurally divergent AICEs to promote gene activation and TH17
differentiation. The AICE motif directs assembly of IRF4 or IRF8
(601565) with BATF heterodimers and is also used in TH2, B, and
dendritic cells. Glasmacher et al. (2012) concluded that this genomic
regulatory element and cognate factors appear to have evolved to
integrate diverse immunomodulatory signals.
GENE STRUCTURE
Hattori et al. (1988) determined that the JUN gene has no introns.
MAPPING
Haluska et al. (1988) isolated a genomic DNA clone encompassing the JUN
gene and used it to determine the chromosomal location. Southern blot
analysis of a rodent-human somatic cell hybrid panel indicated that JUN
is situated on 1p. In situ hybridization narrowed the assignment to
1p32-p31, a chromosomal region involved in both translocations and
deletions in human malignancies. By in situ hybridization, Hattori et
al. (1988) mapped JUN to 1p32-p31.
Mattei et al. (1990) mapped the mouse homolog to chromosome 4. Bahary et
al. (1991) presented molecular genetic linkage maps of mouse chromosome
4 which established the breakpoints in the mouse 4/human 1p region of
homology to a 2-cM interval between Ifa and Jun in mouse and to the
interval between JUN and ACADM (607008) in the human.
ANIMAL MODEL
Hilberg et al. (1993) developed Jun-null mice by gene targeting.
Heterozygous mutant mice appeared normal, but embryos lacking Jun died
between midgestation and late gestation and exhibited impaired
hepatogenesis, altered fetal liver erythropoiesis, and generalized
edema. Jun-defective embryonic stem cells were able to participate in
the development of all somatic cells in chimeric mice except liver
cells, indicating an essential function of Jun in hepatogenesis.
By alanine substitution of ser63 and ser73 of mouse Jun, Behrens et al.
(1999) demonstrated that phosphorylation on these residues was required
for several apoptotic functions. Mouse fibroblasts carrying mutated Jun
had proliferation- and stress-induced apoptotic defects accompanied by
reduced AP1 activity. Mutant mice were smaller than controls, and they
were resistant to epileptic seizures and neuronal apoptosis induced by
the excitotoxic amino acid kainate. Primary mutant neurons were also
protected from apoptosis.
Eferl et al. (2003) used liver-specific inactivation of Jun at different
stages of tumor development to study its role in chemically induced
hepatocellular carcinomas (HCCs) in mice. The requirement for Jun was
restricted to early stages of tumor development, and the number and size
of hepatic tumors was dramatically reduced when Jun was inactivated
after the tumor had initiated. The impaired tumor development correlated
with increased levels of p53 and its target gene Noxa (PMAIP1; 604959),
resulting in the induction of apoptosis without affecting cell
proliferation. Primary hepatocytes lacking Jun showed increased
sensitivity to tumor necrosis factor-alpha (TNF; 191160)-induced
apoptosis, which was abrogated in the absence of p53. These data
indicated that JUN prevents apoptosis by antagonizing p53 activity,
illustrating a mechanism that might contribute to the early stages of
human HCC development.
*FIELD* SA
Bos et al. (1988)
*FIELD* RF
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D. R.; Murphy, K. M.; Singh, H.: A genomic regulatory element that
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essential for normal mouse development and hepatogenesis. Nature 365:
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Reddy, S. V.; Hata, K.; Yamashita, K.; Hiraga, T.; Watanabe, T.; Kukita,
T.; Yoshioka, K.; Rao, A.; Yoneda, T.: Critical roles of c-Jun signaling
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*FIELD* CN
Ada Hamosh - updated: 1/7/2013
Ada Hamosh - updated: 1/28/2011
Patricia A. Hartz - updated: 4/30/2008
Ada Hamosh - updated: 6/29/2007
Ada Hamosh - updated: 2/23/2005
Marla J. F. O'Neill - updated: 1/6/2005
Patricia A. Hartz - updated: 11/22/2004
Ada Hamosh - updated: 6/10/2004
Patricia A. Hartz - updated: 7/8/2003
Patricia A. Hartz - updated: 3/25/2003
Stylianos E. Antonarakis - updated: 2/4/2003
Patricia A. Hartz - updated: 10/30/2002
Patricia A. Hartz - updated: 10/4/2002
Ada Hamosh - updated: 5/8/2002
Stylianos E. Antonarakis - updated: 12/18/2000
*FIELD* CD
Victor A. McKusick: 12/23/1987
*FIELD* ED
terry: 04/04/2013
alopez: 1/7/2013
terry: 1/7/2013
alopez: 2/4/2011
terry: 1/28/2011
mgross: 4/30/2008
wwang: 2/27/2008
ckniffin: 2/5/2008
mgross: 11/14/2007
alopez: 7/2/2007
terry: 6/29/2007
terry: 3/16/2005
alopez: 2/23/2005
carol: 1/7/2005
terry: 1/6/2005
mgross: 11/22/2004
alopez: 6/11/2004
terry: 6/10/2004
mgross: 7/8/2003
mgross: 3/25/2003
mgross: 2/4/2003
mgross: 10/30/2002
mgross: 10/4/2002
carol: 6/20/2002
terry: 6/19/2002
ckniffin: 6/13/2002
alopez: 5/9/2002
terry: 5/8/2002
terry: 12/7/2001
mgross: 12/18/2000
alopez: 11/4/1998
alopez: 10/22/1998
mark: 3/26/1996
mark: 2/15/1996
mark: 7/24/1995
jason: 6/17/1994
supermim: 3/16/1992
carol: 9/6/1991
carol: 10/3/1990
carol: 9/13/1990