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Gene Review

Jun  -  jun proto-oncogene

Mus musculus

Synonyms: AH119, AP-1, AP1, Activator protein 1, Jun A, ...
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Disease relevance of Jun


Psychiatry related information on Jun

  • To further examine what role c-Fos may play in regulating sleep, the present study examined the effects of prolonged wakefulness on c-Fos and AP-1 activity in young (3.5 months old) and old (21.5 months old) Sprague--Dawley rats [6].
  • Valproic acid (VPA), which has demonstrated efficacy in the treatment of bipolar disorder, has been shown to alter components of the phosphoinositide (PI) signaling cascade and to increase gene expression mediated by the transcription factor activator protein 1 (AP-1) [7].

High impact information on Jun

  • Primary hepatocytes lacking c-Jun showed increased sensitivity to TNF-alpha-induced apoptosis, which was abrogated in the absence of p53 [8].
  • Liver-specific inactivation of c-Jun at different stages of tumor development was used to study its role in chemically induced hepatocellular carcinomas (HCCs) in mice [8].
  • The transcription factor c-Jun mediates several cellular processes, including proliferation and survival, and is upregulated in many carcinomas [8].
  • Here we show, by a knock-in strategy and a transgenic complementation approach, that Junb can substitute for absence of Jun during mouse development [9].
  • JunB can substitute for Jun in mouse development and cell proliferation [9].

Chemical compound and disease context of Jun


Biological context of Jun

  • Junb can rescue both liver and cardiac defects in Jun-null mice in a manner dependent on gene dosage [9].
  • These data suggest that the proenkephalin gene may be a physiological target for Fos and Jun in the hippocampus and indicate that these proto-oncogene transcription factors may play a role in neuronal responses to stimulation [15].
  • Different c-Jun N-terminal kinases (JNKs) are activated by a plethora of signals and phosphorylate substrates such as c-Jun, which is required for efficient cell cycle progression [16].
  • JNK catalyzed phosphorylation of c-Jun was also detected in the acini [17].
  • c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms [18].

Anatomical context of Jun


Associations of Jun with chemical compounds


Physical interactions of Jun

  • Rather, c-Jun regulates transcription of p53 negatively by direct binding to a variant AP-1 site in the p53 promoter [26].
  • JNK2 is preferentially bound to c-Jun in unstimulated cells, thereby contributing to c-Jun degradation [16].
  • Electrophoretic mobility shift assay, transcription of the target genes, and Western analysis studies indicated that the increased AP-1 binding activity was attributable to induction of the Jun but not the Fos protein families [27].
  • Antisera to Fos inhibits NF-AT DNA binding as does an oligonucleotide containing a binding site for AP1 [28].
  • Pretreatment of wild-type cells with 5-iodo-6-amino-1,2-benzopyrone, a PARP-1 inhibitor, inhibited JNK activation and DNA binding of AP-1 [29].

Enzymatic interactions of Jun


Regulatory relationships of Jun

  • Inactivation of p53 in c-jun (Deltali*) mice abrogated both hepatocyte cell cycle block and increased p21 protein expression [19].
  • Furthermore, Fra-1 repressed AP-1 activity induced by either TPA or expression of c-Jun and c-Fos [33].
  • TPA and EGF induce transactivation of AP-1 activity in P+ cells but not in P- cells [34].
  • Furthermore, Jun neither enhanced nor inhibited down regulation by Fos [35].
  • Overexpression of c-Jun protein (Jun) could not restore serum-induced DNA synthesis to cells expressing inducible anti-fos RNA despite equivalent transactivation of an AP-1 target gene [36].
  • MEF2 and HDAC4 act to repress c-Jun expression in quiescent VSMCs, protein kinase A enhances this repression, and platelet-derived growth factor derepresses c-Jun expression through calcium/calmodulin-dependent protein kinases and novel protein kinase Cs [37].

Other interactions of Jun

  • Here we show by retroviral-gene transfer that all four Fos proteins, but not the Jun proteins, rescue the differentiation block in vitro [38].
  • Both AP1 and Myc are activated in fibroblasts in response to growth factor stimulation, and various experiments suggest their importance in proliferation [39].
  • We have investigated several candidate pathways implicated in the regulation of p21 expression, and observed increased activity of the stress kinase p38 in regenerating livers of c-jun (Deltali*) mice [19].
  • Consistently, liver regeneration was rescued in c-jun (Deltali*) p21 (-/-) double-mutant mice [19].
  • Comparison of several myogenin mutants for their responsiveness to Fos and Jun shows that repression is directed at the basic-HLH region [40].

Analytical, diagnostic and therapeutic context of Jun


  1. Glucose utilization is essential for hypoxia-inducible factor 1 alpha-dependent phosphorylation of c-Jun. Laderoute, K.R., Calaoagan, J.M., Knapp, M., Johnson, R.S. Mol. Cell. Biol. (2004) [Pubmed]
  2. Overexpression of manganese superoxide dismutase selectively modulates the activity of Jun-associated transcription factors in fibrosarcoma cells. Kiningham, K.K., St Clair, D.K. Cancer Res. (1997) [Pubmed]
  3. c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos. Wang, Z.Q., Liang, J., Schellander, K., Wagner, E.F., Grigoriadis, A.E. Cancer Res. (1995) [Pubmed]
  4. c-Jun inhibits NF-E2 transcriptional activity in association with p18/maf in Friend erythroleukemia cells. Francastel, C., Augery-Bourget, Y., Prenant, M., Walters, M., Martin, D.I., Robert-Lézénès, J. Oncogene (1997) [Pubmed]
  5. Embryonic stem (ES) cells lacking functional c-jun: consequences for growth and differentiation, AP-1 activity and tumorigenicity. Hilberg, F., Wagner, E.F. Oncogene (1992) [Pubmed]
  6. Effects of prolonged wakefulness on c-fos and AP1 activity in young and old rats. Basheer, R., Shiromani, P.J. Brain Res. Mol. Brain Res. (2001) [Pubmed]
  7. Effect of valproic acid on serotonin-2A receptor signaling in C6 glioma cells. Sullivan, N.R., Burke, T., Siafaka-Kapadai, A., Javors, M., Hensler, J.G. J. Neurochem. (2004) [Pubmed]
  8. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Eferl, R., Ricci, R., Kenner, L., Zenz, R., David, J.P., Rath, M., Wagner, E.F. Cell (2003) [Pubmed]
  9. JunB can substitute for Jun in mouse development and cell proliferation. Passegué, E., Jochum, W., Behrens, A., Ricci, R., Wagner, E.F. Nat. Genet. (2002) [Pubmed]
  10. Ultraviolet irradiation, although it activates the transcription factor AP-1 in F9 teratocarcinoma stem cells, does not induce the full complement of differentiation-associated genes. Auer, H.P., König, H., Litfin, M., Stein, B., Rahmsdorf, H.J. Exp. Cell Res. (1994) [Pubmed]
  11. Effect of curcumin on 12-O-tetradecanoylphorbol-13-acetate- and ultraviolet B light-induced expression of c-Jun and c-Fos in JB6 cells and in mouse epidermis. Lu, Y.P., Chang, R.L., Lou, Y.R., Huang, M.T., Newmark, H.L., Reuhl, K.R., Conney, A.H. Carcinogenesis (1994) [Pubmed]
  12. Halofuginone inhibition of COL1A2 promoter activity via a c-Jun-dependent mechanism. McGaha, T.L., Kodera, T., Spiera, H., Stan, A.C., Pines, M., Bona, C.A. Arthritis Rheum. (2002) [Pubmed]
  13. Coordinate regulation of glucocorticoid receptor and c-jun gene expression is cell type-specific and exhibits differential hormonal sensitivity for down- and up-regulation. Barrett, T.J., Vig, E., Vedeckis, W.V. Biochemistry (1996) [Pubmed]
  14. Differential regulation by c-jun and c-fos protooncogenes of hormone response from composite glucocorticoid response element in human papilloma virus type 16 regulatory region. Mittal, R., Kumar, K.U., Pater, A., Pater, M.M. Mol. Endocrinol. (1994) [Pubmed]
  15. Regulation of proenkephalin by Fos and Jun. Sonnenberg, J.L., Rauscher, F.J., Morgan, J.I., Curran, T. Science (1989) [Pubmed]
  16. Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Sabapathy, K., Hochedlinger, K., Nam, S.Y., Bauer, A., Karin, M., Wagner, E.F. Mol. Cell (2004) [Pubmed]
  17. Organization of mammary epithelial cells into 3D acinar structures requires glucocorticoid and JNK signaling. Murtagh, J., McArdle, E., Gilligan, E., Thornton, L., Furlong, F., Martin, F. J. Cell Biol. (2004) [Pubmed]
  18. c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms. Wisdom, R., Johnson, R.S., Moore, C. EMBO J. (1999) [Pubmed]
  19. c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. Stepniak, E., Ricci, R., Eferl, R., Sumara, G., Sumara, I., Rath, M., Hui, L., Wagner, E.F. Genes Dev. (2006) [Pubmed]
  20. Normal peripheral T-cell function in c-Fos-deficient mice. Jain, J., Nalefski, E.A., McCaffrey, P.G., Johnson, R.S., Spiegelman, B.M., Papaioannou, V., Rao, A. Mol. Cell. Biol. (1994) [Pubmed]
  21. Overexpression of Mos, Ras, Src, and Fos inhibits mouse mammary epithelial cell differentiation. Jehn, B., Costello, E., Marti, A., Keon, N., Deane, R., Li, F., Friis, R.R., Burri, P.H., Martin, F., Jaggi, R. Mol. Cell. Biol. (1992) [Pubmed]
  22. Transformation and transactivation suppressor activity of the c-Jun leucine zipper fused to a bacterial repressor. Granger-Schnarr, M., Benusiglio, E., Schnarr, M., Sassone-Corsi, P. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  23. The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including Jun N-terminal protein kinases and p38 kinase by alkylating agents. Wilhelm, D., Bender, K., Knebel, A., Angel, P. Mol. Cell. Biol. (1997) [Pubmed]
  24. Cell transformation by c-fos requires an extended period of expression and is independent of the cell cycle. Miao, G.G., Curran, T. Mol. Cell. Biol. (1994) [Pubmed]
  25. Rapid induction of mitogen-activated protein kinases by immune stimulatory CpG DNA. Yi, A.K., Krieg, A.M. J. Immunol. (1998) [Pubmed]
  26. Control of cell cycle progression by c-Jun is p53 dependent. Schreiber, M., Kolbus, A., Piu, F., Szabowski, A., Möhle-Steinlein, U., Tian, J., Karin, M., Angel, P., Wagner, E.F. Genes Dev. (1999) [Pubmed]
  27. Overexpression of manganese superoxide dismutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model. Zhao, Y., Xue, Y., Oberley, T.D., Kiningham, K.K., Lin, S.M., Yen, H.C., Majima, H., Hines, J., St Clair, D. Cancer Res. (2001) [Pubmed]
  28. Characterization of the nuclear and cytoplasmic components of the lymphoid-specific nuclear factor of activated T cells (NF-AT) complex. Northrop, J.P., Ullman, K.S., Crabtree, G.R. J. Biol. Chem. (1993) [Pubmed]
  29. Poly(ADP-ribose) polymerase-1 regulates activation of activator protein-1 in murine fibroblasts. Andreone, T.L., O'Connor, M., Denenberg, A., Hake, P.W., Zingarelli, B. J. Immunol. (2003) [Pubmed]
  30. Parathyroid hormone-related protein induces insulin expression through activation of MAP kinase-specific phosphatase-1 that dephosphorylates c-Jun NH2-terminal kinase in pancreatic beta-cells. Zhang, B., Hosaka, M., Sawada, Y., Torii, S., Mizutani, S., Ogata, M., Izumi, T., Takeuchi, T. Diabetes (2003) [Pubmed]
  31. Acute cadmium exposure induces stress-related gene expression in wild-type and metallothionein-I/II-null mice. Liu, J., Kadiiska, M.B., Corton, J.C., Qu, W., Waalkes, M.P., Mason, R.P., Liu, Y., Klaassen, C.D. Free Radic. Biol. Med. (2002) [Pubmed]
  32. Trichostatin A activates the osteopontin gene promoter through AP1 site. Sakata, R., Minami, S., Sowa, Y., Yoshida, M., Tamaki, T. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  33. Antitumor promotion by phenolic antioxidants: inhibition of AP-1 activity through induction of Fra expression. Yoshioka, K., Deng, T., Cavigelli, M., Karin, M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  34. Shortage of mitogen-activated protein kinase is responsible for resistance to AP-1 transactivation and transformation in mouse JB6 cells. Huang, C., Ma, W.Y., Young, M.R., Colburn, N., Dong, Z. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  35. Transcriptional activation and repression by Fos are independent functions: the C terminus represses immediate-early gene expression via CArG elements. Gius, D., Cao, X.M., Rauscher, F.J., Cohen, D.R., Curran, T., Sukhatme, V.P. Mol. Cell. Biol. (1990) [Pubmed]
  36. Antisense rescue defines specialized and generalized functional domains for c-Fos protein. Holt, J.T. Mol. Cell. Biol. (1993) [Pubmed]
  37. Protein kinase A-regulated assembly of a MEF2{middle dot}HDAC4 repressor complex controls c-Jun expression in vascular smooth muscle cells. Gordon, J.W., Pagiatakis, C., Salma, J., Du, M., Andreucci, J.J., Zhao, J., Hou, G., Perry, R.L., Dan, Q., Courtman, D., Bendeck, M.P., McDermott, J.C. J. Biol. Chem. (2009) [Pubmed]
  38. Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Matsuo, K., Owens, J.M., Tonko, M., Elliott, C., Chambers, T.J., Wagner, E.F. Nat. Genet. (2000) [Pubmed]
  39. Myc but not Fos rescue of PDGF signalling block caused by kinase-inactive Src. Barone, M.V., Courtneidge, S.A. Nature (1995) [Pubmed]
  40. Fos and Jun repress transcriptional activation by myogenin and MyoD: the amino terminus of Jun can mediate repression. Li, L., Chambard, J.C., Karin, M., Olson, E.N. Genes Dev. (1992) [Pubmed]
  41. Assessment of the role of activator protein-1 on transcription of the mouse steroidogenic acute regulatory protein gene. Manna, P.R., Eubank, D.W., Stocco, D.M. Mol. Endocrinol. (2004) [Pubmed]
  42. Defective nuclear translocation of nuclear factor of activated T cells and extracellular signal-regulated kinase underlies deficient IL-2 gene expression in Wiskott-Aldrich syndrome. Cianferoni, A., Massaad, M., Feske, S., de la Fuente, M.A., Gallego, L., Ramesh, N., Geha, R.S. J. Allergy Clin. Immunol. (2005) [Pubmed]
  43. Identification of a functional AP1 element in the rat vasopressin gene promoter. Yoshida, M., Iwasaki, Y., Asai, M., Takayasu, S., Taguchi, T., Itoi, K., Hashimoto, K., Oiso, Y. Endocrinology (2006) [Pubmed]
  44. A distinct element involved in lipopolysaccharide activation of the tumor necrosis factor-alpha promoter in monocytes. Diaz, B., Lopez-Berestein, G. J. Interferon Cytokine Res. (2000) [Pubmed]
  45. Curcumin derivatives inhibit the formation of Jun-Fos-DNA complex independently of their conserved cysteine residues. Park, C.H., Lee, J.H., Yang, C.H. J. Biochem. Mol. Biol. (2005) [Pubmed]
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