J Appl Biomed 4:163-170, 2006 | DOI: 10.32725/jab.2006.018

Jun: the master regulator in healthy and cancer cells

Petr Vạhara, Jan ©marda*
Laboratory of Cell Differentiation, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Brno, Czech Republic

Healthy cells strictly regulate gene transcription to control crucial cellular regulatory pathways. Members of the Jun protein family, c-Jun, JunB, and JunD are key subunits of the transcription factor AP-1 that controls transcription from various gene promoters. The genes targeted by Jun affect essential life processes, such as cell cycle progression, differentiation or programmed cell death. Therefore, the loss of proper Jun function is often associated with cancer. This review summarizes recent advances in understanding of function of the Jun proteins in healthy and cancer cells.

Keywords: AP-1; Jun; cancer; apoptosis; cell cycle; differentiation

Received: September 25, 2006; Revised: October 5, 2006; Published: July 31, 2006  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Vạhara P, ©marda J. Jun: the master regulator in healthy and cancer cells. J Appl Biomed. 2006;4(4):163-170. doi: 10.32725/jab.2006.018.
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Angel P., Szabowski A., Schorpp-Kistner M.: Function and regulation of AP-1 subunits in skin physiology and pathology. Oncogene 20: 2413-2423, 2001. Go to original source... Go to PubMed...
    2. Behrens A., Jochum W., Sibilia M. et al.: Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation. Oncogene 19:2657-2663, 2000. Go to original source... Go to PubMed...
    3. Behrens A., Sibilia M., David J.P. et al.: Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver. EMBO J. 21:1782-1790, 2002. Go to original source... Go to PubMed...
    4. Behrens A., Sibilia M., Wagner E.F.: Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat. Genet. 21:326-329, 1999. Go to original source... Go to PubMed...
    5. Benbrook D.M., Jones N.C.: Heterodimer formation between CREB and JUN proteins. Oncogene 5:295-302, 1990. Go to PubMed...
    6. Bengal E., Ransone L., Scharfmann R. et al.: Functional antagonism between c-Jun and MyoD proteins: a direct physical association. Cell 68:507-519, 1992. Go to original source... Go to PubMed...
    7. Bernt C., Vennegeerts T., Beuers U. et al.: The human transcription factor AP-1 is a mediator of bile acid-induced liver cell apoptosis. Biochem. Biophys. Res. Commun. 340:800-806, 2006. Go to original source... Go to PubMed...
    8. Black E.J., Walker M., Clark W. et al.: Cell transformation by v-Jun deactivates ERK MAP kinase signalling. Oncogene 21:6540-6548, 2002. Go to original source... Go to PubMed...
    9. Castellazzi M., Spyrou G., La Vista N. et al.: Overexpression of c-jun, junB, or junD affects cell growth differently. Proc. Natl. Acad. Sci. U.S.A. 88:8890-8894, 1991. Go to original source... Go to PubMed...
    10. Cheung N.S., Carroll F.Y., Larm J.A. et al.: Kainate-induced apoptosis correlates with c-Jun activation in cultured cerebellar granule cells. J. Neurosci. Res. 52:69-82, 1998. Go to original source... Go to PubMed...
    11. Cooper S.J., Macgowan J., Ranger-Moore J. et al.: Expression of dominant negative c-jun inhibits ultraviolet B-induced squamous cell carcinoma number and size in an SKH-1 hairless mouse model. Mol. Cancer Res. 1: 848-854, 2003.
    12. Dong Z., Crawford H.C., Lavrovsky V. et al.: A dominant negative mutant of jun blocking 12-O-tetradecanoylphorbol-13-acetate-induced invasion in mouse keratinocytes. Mol. Carcinog. 19:204-212, 1997. Go to original source... Go to PubMed...
    13. Eferl R., Sibilia M., Hilberg F. et al.: Functions of c-Jun in liver and heart development. J. Cell Biol. 145:1049-1061, 1999. Go to original source... Go to PubMed...
    14. Elsasser A., Franzen M., Kohlmann A. et al.: The fusion protein AML1-ETO in acute myeloid leukemia with translocation t(8;21) induces c-jun protein expression via the proximal AP-1 site of the c-jun promoter in an indirect, JNK-dependent manner. Oncogene 22:5646-5657, 2003. Go to original source... Go to PubMed...
    15. Estus S., Zaks W.J., Freeman R.S et al.: Altered gene expression in neurons during programmed cell death: identification of c-jun as necessary for neuronal apoptosis. J. Cell Biol. 127:1717-1727, 1994. Go to original source... Go to PubMed...
    16. Fialka I., Schwarz H., Reichmann E. et al.: The estrogen-dependent c-JunER protein causes a reversible loss of mammary epithelial cell polarity involving a destabilization of adherens junctions. J. Cell Biol. 132:1115-1132, 1996. Go to original source... Go to PubMed...
    17. Finch S., Joseloff E., Bowden T.: JunB negatively regulates AP-1 activity and cell proliferation of malignant mouse keratinocytes. J. Cancer Res. Clin. Oncol. 128:3-10, 2002. Go to original source... Go to PubMed...
    18. Florin L., Hummerich L., Dittrich B.T. et al.: Identification of novel AP-1 target genes in fibroblasts regulated during cutaneous wound healing. Oncogene 23:7005-7017, 2004. Go to original source... Go to PubMed...
    19. Florin L., Knebel J., Zigrino P. et al.: Delayed wound healing and epidermal hyperproliferation in mice lacking JunB in the skin. J. Invest. Dermatol. 126:902-911, 2006. Go to original source... Go to PubMed...
    20. Gaub M. P., Bellard M., Scheuer I. et al.: Activation of the ovalbumin gene by the estrogen receptor involves the fos-jun complex. Cell 63:1267-1276, 1990. Go to original source... Go to PubMed...
    21. Grigoriadis A.E., Schellander K., Wang Z.Q., Wagner E.F.: Osteoblasts are target cells for transformation in c-fos transgenic mice. J. Cell Biol. 122:685-701, 1993. Go to original source... Go to PubMed...
    22. Ham J., Babij C., Whitfield J. et al.: A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death. Neuron 14:927-939, 1995. Go to original source... Go to PubMed...
    23. Hartl M., Reiter F., Bader A.G. et al.: JAC, a direct target of oncogenic transcription factor Jun, is involved in cell transformation and tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 98:13601-13606, 2001. Go to original source... Go to PubMed...
    24. Hibi M., Lin A., Smeal T. et al.: Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 7:2135-2148, 1993. Go to original source... Go to PubMed...
    25. Hilberg F., Aguzzi A., Howells N., Wagner E.F.: c-jun is essential for normal mouse development and hepatogenesis. Nature 365: 179-181, 1993. Go to original source... Go to PubMed...
    26. Hilfiker-Kleiner D., Hilfiker A., Kaminski K. et al.: Lack of JunD promotes pressure overload-induced apoptosis, hypertrophic growth, and angiogenesis in the heart. Circulation 112: 1470-1477, 2005. Go to original source... Go to PubMed...
    27. Inagaki N., Maekawa T., Sudo T. et al.: c-Jun represses the human insulin promoter activity that depends on multiple cAMP response elements. Proc. Natl. Acad. Sci. U.S.A. 89: 1045-1049, 1992. Go to original source... Go to PubMed...
    28. Jochum W., Passegue E., Wagner E.F.: AP-1 in mouse development and tumorigenesis. Oncogene 20:2401-2412, 2001. Go to original source... Go to PubMed...
    29. Johnson R., Spiegelman B., Hanahan D., Wisdom R.: Cellular transformation and malignancy induced by ras require c-jun. Mol. Cell Biol. 16:4504-4511, 1996. Go to original source... Go to PubMed...
    30. Johnson R.S., Van Lingen B., Papaioannou V.E., Spiegelman B. M.: A null mutation at the c-jun locus causes embryonic lethality and retarded cell growth in culture. Genes Dev. 7: 1309-1317, 1993. Go to original source... Go to PubMed...
    31. Jonat C., Rahmsdorf H.J., Park K.K., Cato A.C., Gebel S., Ponta H., Herrlich P.: Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell 62:1189-1204, 1990. Go to original source... Go to PubMed...
    32. Kanamoto T., Mota M., Takeda K. et al.: Role of apoptosis signal-regulating kinase in regulation of the c-Jun N-terminal kinase pathway and apoptosis in sympathetic neurons. Mol. Cell Biol. 20:196-204, 2000. Go to original source... Go to PubMed...
    33. Karin M., Liu Z., Zandi E.: AP-1 function and regulation. Curr. Opin. Cell Biol. 9:240-246, 1997. Go to original source... Go to PubMed...
    34. Kolbus A., Herr I., Schreiber M. et al.: C-Jun-dependent CD95-L expression is a rate-limiting step in the induction of apoptosis by alkylating agents. Mol. Cell. Biol. 20:575-582, 2000. Go to original source... Go to PubMed...
    35. Kouzarides T., Ziff E.: Leucine zippers of fos, jun and GCN4 dictate dimerization specificity and thereby control DNA binding. Nature 340: 568-571, 1989. Go to original source... Go to PubMed...
    36. Leaner V.D., Kinoshita I., Birrer M.J.: AP-1 complexes containing cJun and JunB cause cellular transformation of Rat1a fibroblasts and share transcriptional targets. Oncogene 22:5619-5629, 2003. Go to original source... Go to PubMed...
    37. Lee W., Mitchell P., Tjian R.: Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell 49:741-52, 1987. Go to original source... Go to PubMed...
    38. Liu Y., Ludes-Meyers J., Zhang Y. et al.: Inhibition of AP-1 transcription factor causes blockade of multiple signal transduction pathways and inhibits breast cancer growth. Oncogene 21: 7680-7689, 2002. Go to original source... Go to PubMed...
    39. Lloyd A., Yancheva N., Wasylyk B.: Transformation suppressor activity of a Jun transcription factor lacking its activation domain. Nature 352:635-638, 1991. Go to original source... Go to PubMed...
    40. Ludes-Meyers J.H., Liu Y., Munoz-Medellin D. et al.: AP-1 blockade inhibits the growth of normal and malignant breast cells. Oncogene 20:2771-2780, 2001. Go to original source... Go to PubMed...
    41. Macian F., Lopez-Rodriguez C., Rao A.: Partners in transcription: NFAT and AP-1. Oncogene 20: 2476-2489, 2001. Go to original source... Go to PubMed...
    42. MacLaren A., Clark W., Black E.J. et al.: v-Jun stimulates both cdk2 kinase activity and G1/S progression via transcriptional repression of p21 CIP1. Oncogene 22:2383-2395, 2003. Go to original source... Go to PubMed...
    43. Maeno K., Masuda A., Yanagisawa K. et al.: Altered regulation of c-jun and its involvement in anchorage-independent growth of human lung cancers. Oncogene 25:271-277, 2006. Go to original source... Go to PubMed...
    44. Marshall G.M., Vanhamme L., Wong W.Y., Su H., Vogt P.K.: Wounding acts as a tumor promoter in chickens inoculated with avian sarcoma virus 17. Virology 188:373-377, 1992. Go to original source... Go to PubMed...
    45. Marshall G. M., Vanhamme L.: Characterization of sarcoma cell lines from v-jun transgenic mice. Cancer Res. 53:622-626, 1993.
    46. Naruishi K., Nishimura F., Yamada-Naruishi H., Omori K., Yamaguchi M., Takashiba S.: C-jun N-terminal kinase (JNK) inhibitor, SP600125, blocks interleukin (IL)-6-induced vascular endothelial growth factor (VEGF) production: cyclosporine A partially mimics this inhibitory effect. Transplantation 76:1380-1382, 2003. Go to original source... Go to PubMed...
    47. Nead M.A., Baglia L. A., Antinore M.J., Ludlow J.W., McCance D.J.: Rb binds c-Jun and activates transcription. EMBO J. 17:2342-2352, 1998. Go to original source... Go to PubMed...
    48. Neyns B., Teugels E., Bourgain C. et al.: Alteration of jun proto-oncogene status by plasmid transfection affects growth of human ovarian cancer cells. Int. J. Cancer 82: 687-693, 1999. Go to original source...
    49. Nishimura T., Vogt P.K.: The avian cellular homolog of the oncogene jun. Oncogene 3: 659-663, 1988. Go to PubMed...
    50. Passegue E., Jochum W., Schorpp-Kistner M. et al.: Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking junB expression in the myeloid lineage. Cell 104: 21-32, 2001. Go to original source... Go to PubMed...
    51. Passegue E., Wagner E.F.: JunB suppresses cell proliferation by transcriptional activation of p16(INK4a) expression. EMBO J. 19:2969-2979, 2000. Go to original source... Go to PubMed...
    52. Pfarr C.M., Mechta F., Spyrou G. et al.: Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras. Cell 76:747-60, 1994. Go to original source... Go to PubMed...
    53. Poindessous-Jazat V., Augery-Bourget Y., Robert-Lezenes J.: c-Jun modulates apoptosis but not terminal cell differentiation in murine erythroleukemia cells. Leukemia 16:233-243, 2002. Go to original source... Go to PubMed...
    54. Qiao L., Han S.I., Fang Y. et al.: Bile acid regulation of C/EBPbeta, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Mol. Cell. Biol. 23:3052-3066, 2003. Go to original source... Go to PubMed...
    55. Rahmsdorf H.J: Jun: transcription factor and oncoprotein. J. Mol. Med. 74:725-747, 1996. Go to original source... Go to PubMed...
    56. Raitano A.B., Halpern J.R., Hambuch T.M., Sawyers C.L.: The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation. Proc. Natl. Acad. Sci. U.S.A. 92:11746-11750, 1995. Go to original source... Go to PubMed...
    57. Rangatia J., Vangala R.K., Singh S.M. et al.: c-Jun expression in acute myeloid leukemias inhibits C/EBPalpha DNA binding via leucine zipper domain interaction. Oncogene 22:4760-4764, 2003. Go to original source... Go to PubMed...
    58. Ricci R., Eriksson U., Oudit G.Y. et al.: Distinct functions of junD in cardiac hypertrophy and heart failure. Genes Dev. 19:208-213, 2005. Go to original source... Go to PubMed...
    59. Rinehart-Kim J., Johnston M., Birrer M., Bos T.: Alterations in the gene expression profile of MCF-7 breast tumor cells in response to c-Jun. Int. J. Cancer 88:180-190, 2000. Go to original source... Go to PubMed...
    60. Roffler-Tarlov S., Brown J.J., Tarlov E. et al.: Programmed cell death in the absence of c-Fos and c-Jun. Development 122:1-9, 1996. Go to original source... Go to PubMed...
    61. Rossant J.: Mouse mutants and cardiac development: new molecular insights into cardiogenesis. Circ. Res. 78:349-353, 1996. Go to original source... Go to PubMed...
    62. Schorpp-Kistner M., Wang Z.Q., Angel P., Wagner E.F.: JunB is essential for mammalian placentation. EMBO J. 18:934-948, 1999. Go to original source... Go to PubMed...
    63. Schreiber M., Kolbus A., Piu F et al.: Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev. 13: 607-619, 1999. Go to original source... Go to PubMed...
    64. Schuh A.C., Keating S.J., Monteclaro F.S. et al.: Obligatory wounding requirement for tumorigenesis in v-jun transgenic mice. Nature 346:756-760, 1990. Go to original source... Go to PubMed...
    65. Schüle R., Rangarajan P., Kliewer S. et al.: Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor. Cell 62: 217-226, 1990. Go to original source... Go to PubMed...
    66. Schütte J., Minna J.D., Birrer M.J.: Deregulated expression of human c-jun transforms primary rat embryo cells in cooperation with an activated c-Ha-ras gene and transforms rat-1a cells as a single gene. Proc. Natl. Acad. Sci. U.S.A. 86: 2257-2261, 1989. Go to original source... Go to PubMed...
    67. ©evèíková S., Souèek K., Kubala L. et al.: Differential effects of v-Jun and c-Jun proteins on v-myb-transformed monoblasts. Cell. Mol. Life Sci. 59:1690-1705, 2002. Go to original source...
    68. Shaulian E., Karin M.: AP-1 in cell proliferation and survival. Oncogene 20:2390-2400, 2001. Go to original source... Go to PubMed...
    69. Shirai K., Okada Y., Saika S., Senba E., Ohnishi Y.: Expression of transcription factor AP-1 in rat lens epithelial cells during wound repair. Exp. Eye Res. 73:461-468, 2001. Go to original source... Go to PubMed...
    70. Smeal T., Binetruy B., Mercola D. et al.: Oncoprotein-mediated signalling cascade stimulates c-Jun activity by phosphorylation of serines 63 and 73. Mol. Cell. Biol. 12: 3507-3513, 1992. Go to original source... Go to PubMed...
    71. Smeal T., Binetruy B., Mercola D.A. et al.: Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature 354:494-496, 1991. Go to original source... Go to PubMed...
    72. Suto R., Tominaga K., Mizuguchi H. et al.: Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer. Gene Ther. 11:187-193, 2004. Go to original source... Go to PubMed...
    73. Szabo E., Riffe M.E., Steinberg S.M., Birrer M.J., Linnoila R.I.: Altered cJUN expression: an early event in human lung carcinogenesis. Cancer Res. 56:305-315, 1996. Go to PubMed...
    74. Szabowski A., Maas-Szabowski N., Andrecht S. et al.: c-Jun and JunB antagonistically control cytokine-regulated mesenchymal-epidermal interaction in skin. Cell 103:745-755, 2000. Go to original source... Go to PubMed...
    75. Thepot D., Weitzman J.B., Barra J. et al.: Targeted disruption of the murine junD gene results in multiple defects in male reproductive function. Development 127:143-153, 2000. Go to original source... Go to PubMed...
    76. Tsai E., Yie J., Thanos D., Goldfeld A.E.: Cell-type-specific regulation of the human tumor necrosis factor alpha gene in B cells and T cells by NFATp and ATF-2/JUN. Mol. Cell. Biol. 16:5232-5244, 1996. Go to original source... Go to PubMed...
    77. Wang Z.Q., Liang J., Schellander K. et al.: c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos. Cancer Res. 55:6244-6251, 1995.
    78. Watts R.G., Ben-Ari E.T., Bernstein L.R. et al.: c-jun and multistage carcinogenesis: association of overexpression of introduced c-jun with progression toward a neoplastic endpoint in mouse JB6 cells sensitive to tumor promoter-induced transformation. Mol. Carcinog. 13: 27-36, 1995. Go to original source... Go to PubMed...
    79. Weitzman J.B., Fiette L., Matsuo K., Yaniv M.: JunD protects cells from p53-dependent senescence and apoptosis. Mol. Cell 6:1109-1119, 2000. Go to original source... Go to PubMed...
    80. Wiggan O., Hamel P.A.: Pax3 regulates morphogenetic cell behavior in vitro coincident with activation of a PCP/non-canonical Wnt-signalling cascade. J. Cell Sci. 115:531-541, 2002. Go to original source... Go to PubMed...
    81. Wilkinson D.G., Bhatt S., Ryseck R.P., Bravo R.: Tissue-specific expression of c-jun and junB during organogenesis in the mouse. Development 106:465-471, 1989. Go to original source... Go to PubMed...
    82. Yang L., Kim H.T., Munoz-Medellin D. et al.: Induction of retinoid resistance in breast cancer cells by overexpression of cJun. Cancer Res. 57:4652-4661, 1997. Go to PubMed...
    83. Yasumoto H., Kim S., Zhan Y. et al.: Negative c-jun gene transfer inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia in rats. Gene Ther. 8:1682-1689, 2001. Go to original source... Go to PubMed...
    84. Young M.R., Li J.J., Rincon M. et al.: Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc. Natl. Acad. Sci. U.S.A. 96: 9827-9832, 1999. Go to original source... Go to PubMed...
    85. Zhou F., Thompson E.B.: Role of c-jun induction in the glucocorticoid-evoked apoptotic pathway in human leukemic lymphoblasts. Mol. Endocrinol. 10:306-316, 1996. Go to original source... Go to PubMed...

    Return to the content