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Gene Review

JUN  -  jun proto-oncogene

Homo sapiens

Synonyms: AP-1, AP1, Activator protein 1, Proto-oncogene c-Jun, Transcription factor AP-1, ...
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Disease relevance of JUN

  • Also, although all four oncoprotein pairs were expressed significantly more often in adenocarcinomas, only RAS/JUN was significantly coexpressed in the large tubulovillous adenomas [1].
  • Immunohistochemical detection of RAS, JUN, FOS, and p53 oncoprotein expression in human colorectal adenomas and carcinomas [1].
  • Of the four oncoprotein pairs, only RAS/JUN was significantly coexpressed in large tubulovillous adenomas [1].
  • Coordinate activation of activator protein 1 and inflammatory cytokines in response to Neisseria gonorrhoeae epithelial cell contact involves stress response kinases [2].
  • At a dose range (12.5-50 micromol/L) that inhibited cell transformation, SC-236 also inhibited anchorage-independent cell growth and AP-1-activation in 3 gastric cancer cells, independent of COX-prostaglandin synthesis [3].

Psychiatry related information on JUN

  • In order to approach the astroglial implication of addictive and neurotoxic processes associated with psychostimulant drug abuse, the effects of amphetamine or cocaine (1-100 microM) on redox status, AP-1 transcription factor and pro-enkephalin, an AP-1 target gene, were investigated in the human astrocyte-like U373 MG cells [4].
  • The transcription factors NF-kappa B and AP-1 have been implicated in the inducible expression of a variety of genes involved in responses to oxidative stress and cellular defense mechanisms [5].
  • Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease [6].
  • In this study, we examined the effects of AMPH (5mg/kg), PCP (5mg/kg) and their combination (5mg/kg each) on rat motor activity as well as on the activation of the AP-1 transcription factor in rat brains [7].

High impact information on JUN

  • NFAT is also notable for its ability to bind cooperatively with transcription factors of the AP-1 (Fos/Jun) family to composite NFAT:AP-1 sites, found in the regulatory regions of many genes that are inducibly transcribed by immune-system cells [8].
  • To elucidate dimer-specific functions of the AP-1 family of transcription factors, we reconstituted skin by combining primary human keratinocytes and mouse wild-type, c-jun(-/-), and junB(-/-) fibroblasts [9].
  • These data suggest that the relative activation state of these AP-1 subunits in a non-cell-autonomous, transregulatory fashion directs regeneration of the epidermis and maintenance of tissue homeostasis in skin [9].
  • Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription [10].
  • The ultraviolet (UV) response of mammalian cells is characterized by a rapid and selective increase in gene expression mediated by AP-1 and NF-kappa B. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain [11].

Chemical compound and disease context of JUN


Biological context of JUN

  • Phorbol ester-induced amino-terminal phosphorylation of human JUN but not JUNB regulates transcriptional activation [17].
  • Mutational analysis indicates that serine-63 and -73, which reside within the putative regulatory domain of JUN, are required for both constitutive and phorbol 12-myristate 13-acetate-inducible N-terminal JUN phosphorylation [17].
  • Using MKK4 somatic human knockout cancer cells, we observed the proof-of-principle in the downstream gene dosage-dependent phenotypes: heterozygous and homozygous knockouts were progressively deficient in Mkk4 protein, in stress-induced phosphorylation of Jnk, and the resultant upregulation of JUN mRNA [18].
  • Cytokine genes and a variety of other immune response genes are activated as a result of the regulatory function of immediate early response transcription factors including activator protein 1 (AP-1) [2].
  • We found that dexamethasone (Dex) effectively suppressed T cell receptor-induced (TCR-induced) proliferation of naive CD4+ T cells, through a mechanism involving downregulation of c-Fos expression and inhibition of activator protein-1 (AP-1), nuclear factor of activated T cells (NF-AT), and NF-kappaB transcriptional activity [19].

Anatomical context of JUN

  • Functional consequences of these effects were suggested by the inhibition of AP-1 binding in hypoxic HT29 cells in the presence of GA [12].
  • Among eight human glioma cell lines, cellular mRNA levels of transcription factors SP-1 and AP-1 (c-Fos and c-Jun) were found to be closely correlated with those of VEGF [20].
  • These studies show that in normal human keratinocytes EGCG markedly increases, via a MAPK signaling mechanism, AP1 factor-associated responses [21].
  • Ultraviolet irradiation induces Smad7 via induction of transcription factor AP-1 in human skin fibroblasts [22].
  • In addition, anti-HA antibody co-precipitated c-Jun from HeLa cells co-expressing c-Jun and HA-tagged Bcl3, consistent with the idea that Bcl3 directly associates with AP-1 in vivo [23].

Associations of JUN with chemical compounds

  • AP-1 function is antagonized by activated members of the steroid/thyroid hormone receptor superfamily [24].
  • An increase in the basal levels of AP-1 DNA binding was also detected in the nuclei from steroid-resistant asthmatic patients [25].
  • Cyclooxygenase-2 inhibitor (SC-236) suppresses activator protein-1 through c-Jun NH2-terminal kinase [3].
  • BACKGROUND AND AIMS: Aspirin exerts antitumor effect partly through blocking tumor promoter-induced activator protein-1 (AP-1) activation [3].
  • Retinoids exhibit antineoplastic activities that may be linked to retinoid receptor-mediated transrepression of activating protein 1 (AP1), a heterodimeric transcription factor composed of fos- and jun-related proteins [26].

Physical interactions of JUN


Regulatory relationships of JUN


Other interactions of JUN


Analytical, diagnostic and therapeutic context of JUN


  1. Immunohistochemical detection of RAS, JUN, FOS, and p53 oncoprotein expression in human colorectal adenomas and carcinomas. Magrisso, I.J., Richmond, R.E., Carter, J.H., Pross, C.B., Gilfillen, R.A., Carter, H.W. Lab. Invest. (1993) [Pubmed]
  2. Coordinate activation of activator protein 1 and inflammatory cytokines in response to Neisseria gonorrhoeae epithelial cell contact involves stress response kinases. Naumann, M., Rudel, T., Wieland, B., Bartsch, C., Meyer, T.F. J. Exp. Med. (1998) [Pubmed]
  3. Cyclooxygenase-2 inhibitor (SC-236) suppresses activator protein-1 through c-Jun NH2-terminal kinase. Wong, B.C., Jiang, X.H., Lin, M.C., Tu, S.P., Cui, J.T., Jiang, S.H., Wong, W.M., Yuen, M.F., Lam, S.K., Kung, H.F. Gastroenterology (2004) [Pubmed]
  4. Effect of acute and chronic psychostimulant drugs on redox status, AP-1 activation and pro-enkephalin mRNA in the human astrocyte-like U373 MG cells. Malaplate-Armand, C., Becuwe, P., Ferrari, L., Masson, C., Dauça, M., Visvikis, S., Lambert, H., Batt, A.M. Neuropharmacology (2005) [Pubmed]
  5. Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-kappa B and AP-1. Schenk, H., Klein, M., Erdbrügger, W., Dröge, W., Schulze-Osthoff, K. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  6. Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease. Rademakers, R., Sleegers, K., Theuns, J., Van den Broeck, M., Bel Kacem, S., Nilsson, L.G., Adolfsson, R., van Duijn, C.M., Van Broeckhoven, C., Cruts, M. Neurobiol. Aging (2005) [Pubmed]
  7. Enhancement of AP-1 DNA-binding activity during amphetamine- and phencyclidine-mediated behaviour in rats. Milanovic, D., Pesic, V., Rakic, L., Kanazir, S., Ruzdijic, S. Neuropharmacology (2006) [Pubmed]
  8. Transcription factors of the NFAT family: regulation and function. Rao, A., Luo, C., Hogan, P.G. Annu. Rev. Immunol. (1997) [Pubmed]
  9. c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin. Szabowski, A., Maas-Szabowski, N., Andrecht, S., Kolbus, A., Schorpp-Kistner, M., Fusenig, N.E., Angel, P. Cell (2000) [Pubmed]
  10. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Agarwal, S.K., Guru, S.C., Heppner, C., Erdos, M.R., Collins, R.M., Park, S.Y., Saggar, S., Chandrasekharappa, S.C., Collins, F.S., Spiegel, A.M., Marx, S.J., Burns, A.L. Cell (1999) [Pubmed]
  11. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Dérijard, B., Hibi, M., Wu, I.H., Barrett, T., Su, B., Deng, T., Karin, M., Davis, R.J. Cell (1994) [Pubmed]
  12. Effects of geldanamycin on signaling through activator-protein 1 in hypoxic HT29 human colon adenocarcinoma cells. Vasilevskaya, I.A., O'Dwyer, P.J. Cancer Res. (1999) [Pubmed]
  13. FRA-1 expression level modulates regulation of activator protein-1 activity by estradiol in breast cancer cells. Philips, A., Teyssier, C., Galtier, F., Rivier-Covas, C., Rey, J.M., Rochefort, H., Chalbos, D. Mol. Endocrinol. (1998) [Pubmed]
  14. NF-kappaB- and AP-1-mediated induction of human beta defensin-2 in intestinal epithelial cells by Escherichia coli Nissle 1917: a novel effect of a probiotic bacterium. Wehkamp, J., Harder, J., Wehkamp, K., Wehkamp-von Meissner, B., Schlee, M., Enders, C., Sonnenborn, U., Nuding, S., Bengmark, S., Fellermann, K., Schröder, J.M., Stange, E.F. Infect. Immun. (2004) [Pubmed]
  15. alpha-Lipoic acid and N-acetyl cysteine prevent zinc deficiency-induced activation of NF-kappaB and AP-1 transcription factors in human neuroblastoma IMR-32 cells. Mackenzie, G.G., Zago, M.P., Erlejman, A.G., Aimo, L., Keen, C.L., Oteiza, P.I. Free Radic. Res. (2006) [Pubmed]
  16. Quercetin glucuronide prevents VSMC hypertrophy by angiotensin II via the inhibition of JNK and AP-1 signaling pathway. Yoshizumi, M., Tsuchiya, K., Suzaki, Y., Kirima, K., Kyaw, M., Moon, J.H., Terao, J., Tamaki, T. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  17. Phorbol ester-induced amino-terminal phosphorylation of human JUN but not JUNB regulates transcriptional activation. Franklin, C.C., Sanchez, V., Wagner, F., Woodgett, J.R., Kraft, A.S. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  18. Theoretical proposal: allele dosage of MAP2K4/MKK4 could rationalize frequent 17p loss in diverse human cancers. Cunningham, S.C., Gallmeier, E., Hucl, T., Dezentje, D.A., Abdelmohsen, K., Gorospe, M., Kern, S.E. Cell Cycle (2006) [Pubmed]
  19. Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4+ T cells. Tsitoura, D.C., Rothman, P.B. J. Clin. Invest. (2004) [Pubmed]
  20. Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of SP-1. Ryuto, M., Ono, M., Izumi, H., Yoshida, S., Weich, H.A., Kohno, K., Kuwano, M. J. Biol. Chem. (1996) [Pubmed]
  21. Green tea polyphenol stimulates a Ras, MEKK1, MEK3, and p38 cascade to increase activator protein 1 factor-dependent involucrin gene expression in normal human keratinocytes. Balasubramanian, S., Efimova, T., Eckert, R.L. J. Biol. Chem. (2002) [Pubmed]
  22. Ultraviolet irradiation induces Smad7 via induction of transcription factor AP-1 in human skin fibroblasts. Quan, T., He, T., Voorhees, J.J., Fisher, G.J. J. Biol. Chem. (2005) [Pubmed]
  23. Bcl3, an IkappaB protein, stimulates activating protein-1 transactivation and cellular proliferation. Na, S.Y., Choi, J.E., Kim, H.J., Jhun, B.H., Lee, Y.C., Lee, J.W. J. Biol. Chem. (1999) [Pubmed]
  24. Nuclear hormone receptor antagonism with AP-1 by inhibition of the JNK pathway. Caelles, C., González-Sancho, J.M., Muñoz, A. Genes Dev. (1997) [Pubmed]
  25. Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma. Adcock, I.M., Lane, S.J., Brown, C.R., Lee, T.H., Barnes, P.J. J. Exp. Med. (1995) [Pubmed]
  26. Retinoic acid receptors inhibit AP1 activation by regulating extracellular signal-regulated kinase and CBP recruitment to an AP1-responsive promoter. Benkoussa, M., Brand, C., Delmotte, M.H., Formstecher, P., Lefebvre, P. Mol. Cell. Biol. (2002) [Pubmed]
  27. Induction of the angiogenic modulator fibroblast growth factor-binding protein by epidermal growth factor is mediated through both MEK/ERK and p38 signal transduction pathways. Harris, V.K., Coticchia, C.M., Kagan, B.L., Ahmad, S., Wellstein, A., Riegel, A.T. J. Biol. Chem. (2000) [Pubmed]
  28. Regulation of JNK by MKK-7 in fibroblast-like synoviocytes. Inoue, T., Hammaker, D., Boyle, D.L., Firestein, G.S. Arthritis Rheum. (2006) [Pubmed]
  29. Receptor-interacting protein 140 binds c-Jun and inhibits estradiol-induced activator protein-1 activity by reversing glucocorticoid receptor-interacting protein 1 effect. Teyssier, C., Belguise, K., Galtier, F., Cavailles, V., Chalbos, D. Mol. Endocrinol. (2003) [Pubmed]
  30. CREB binding protein is a coactivator for the androgen receptor and mediates cross-talk with AP-1. Frønsdal, K., Engedal, N., Slagsvold, T., Saatcioglu, F. J. Biol. Chem. (1998) [Pubmed]
  31. AP-1 and Oct-1 transcription factors down-regulate the expression of the human PIT1/GHF1 gene. Delhase, M., Castrillo, J.L., de la Hoya, M., Rajas, F., Hooghe-Peters, E.L. J. Biol. Chem. (1996) [Pubmed]
  32. Prolactin and estrogen enhance the activity of activating protein 1 in breast cancer cells: role of extracellularly regulated kinase 1/2-mediated signals to c-fos. Gutzman, J.H., Nikolai, S.E., Rugowski, D.E., Watters, J.J., Schuler, L.A. Mol. Endocrinol. (2005) [Pubmed]
  33. Ras and mitogen-activated protein kinase kinase kinase-1 coregulate activator protein-1- and nuclear factor-kappaB-mediated gene expression in airway epithelial cells. Zhou, L., Tan, A., Iasvovskaia, S., Li, J., Lin, A., Hershenson, M.B. Am. J. Respir. Cell Mol. Biol. (2003) [Pubmed]
  34. Hepatocyte survival in acute hepatitis is due to c-Jun/AP-1-dependent expression of inducible nitric oxide synthase. Hasselblatt, P., Rath, M., Komnenovic, V., Zatloukal, K., Wagner, E.F. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  35. c-Jun supports ribosomal RNA processing and nucleolar localization of RNA helicase DDX21. Holmström, T.H., Mialon, A., Kallio, M., Nymalm, Y., Mannermaa, L., Holm, T., Johansson, H., Black, E., Gillespie, D., Salminen, T.A., Langel, U., Valdez, B.C., Westermarck, J. J. Biol. Chem. (2008) [Pubmed]
  36. Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Hu, M.C., Qiu, W.R., Wang, X., Meyer, C.F., Tan, T.H. Genes Dev. (1996) [Pubmed]
  37. HIV-1 Nef-induced FasL induction and bystander killing requires p38 MAPK activation. Muthumani, K., Choo, A.Y., Hwang, D.S., Premkumar, A., Dayes, N.S., Harris, C., Green, D.R., Wadsworth, S.A., Siekierka, J.J., Weiner, D.B. Blood (2005) [Pubmed]
  38. Transient stimulation of the c-Jun-NH2-terminal kinase/activator protein 1 pathway and inhibition of extracellular signal-regulated kinase are early effects in paclitaxel-mediated apoptosis in human B lymphoblasts. Amato, S.F., Swart, J.M., Berg, M., Wanebo, H.J., Mehta, S.R., Chiles, T.C. Cancer Res. (1998) [Pubmed]
  39. Interactions between adenovirus E1A and members of the AP-1 family of cellular transcription factors. Maguire, K., Shi, X.P., Horikoshi, N., Rappaport, J., Rosenberg, M., Weinmann, R. Oncogene (1991) [Pubmed]
  40. ERK MAP kinase links cytokine signals to activation of latent HIV-1 infection by stimulating a cooperative interaction of AP-1 and NF-kappaB. Yang, X., Chen, Y., Gabuzda, D. J. Biol. Chem. (1999) [Pubmed]
  41. Inhibition of AP-1 by the glucocorticoid-inducible protein GILZ. Mittelstadt, P.R., Ashwell, J.D. J. Biol. Chem. (2001) [Pubmed]
  42. Global gene expression analysis of estrogen receptor transcription factor cross talk in breast cancer: identification of estrogen-induced/activator protein-1-dependent genes. DeNardo, D.G., Kim, H.T., Hilsenbeck, S., Cuba, V., Tsimelzon, A., Brown, P.H. Mol. Endocrinol. (2005) [Pubmed]
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