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.
AP-1; Jun; cancer; apoptosis; cell cycle; differentiation
Angel P, Szabowski A, Schorpp-Kistner M: Function and regulation of AP-1 subunits in skin physiology and pathology. Oncogene 20:2413-2423, 2001.
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.
Behrens A, Sibilia M, David JP et al.: Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver. EMBO J 21:1782-1790, 2002.
Behrens A, Sibilia M, Wagner EF: Aminoterminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 21:326-329, 1999.
Benbrook DM, Jones NC: Heterodimer formation between CREB and JUN proteins. Oncogene 5:295-302, 1990.
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.
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.
Black EJ, Walker M, Clark W et al.: Cell transformation by v-Jun deactivates ERK MAP kinase signalling. Oncogene 21:6540-6548, 2002.
Castellazzi M, Spyrou G, La Vista N et al.: Overexpression of c-jun, junB, or junD affects cell growth differently. Proc Natl Acad Sci USA 88:8890-8894, 1991.
Cheung NS, Carroll FY, Larm JA et al.: Kainate-induced apoptosis correlates with c-Jun activation in cultured cerebellar granule cells. J Neurosci Res 52:69-82, 1998.
Cooper SJ, 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.
Dong Z, Crawford HC, 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.
Eferl R, Sibilia M, Hilberg F et al.: Functions of c-Jun in liver and heart development. J Cell Biol 145:1049-1061, 1999.
Elsasser A, Franzen M, Kohlmann A et al.: The fusion protein AML1-ETO in acute myeloid leukemia with translocation t(8;21) induces cjun protein expression via the proximal AP-1 site of the c-jun promoter in an indirect, JNKdependent manner. Oncogene 22:5646-5657, 2003.
Estus S, Zaks WJ, Freeman RS 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.
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.
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.
Florin L, Hummerich L, Dittrich BT et al.: Identification of novel AP-1 target genes in fibroblasts regulated during cutaneous wound healing. Oncogene 23:7005-7017, 2004.
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.
Gaub MP, 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.
Grigoriadis AE, Schellander K, Wang ZQ, Wagner EF: Osteoblasts are target cells for transformation in c-fos transgenic mice. J Cell Biol 122:685-701, 1993.
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.
Hartl M, Reiter F, Bader AG et al.: JAC, a direct target of oncogenic transcription factor Jun, is involved in cell transformation and tumorigenesis. Proc Natl Acad Sci USA 98:13601-13606, 2001.
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.
Hilberg F, Aguzzi A, Howells N, Wagner EF: c-jun is essential for normal mouse development and hepatogenesis. Nature 365:179-181, 1993.
Hilfiker-Kleiner D, Hilfiker A, Kaminski K et al.: Lack of JunD promotes pressure overloadinduced apoptosis, hypertrophic growth, and angiogenesis in the heart. Circulation 112:1470-1477, 2005.
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 USA 89:1045-1049, 1992.
Jochum W, Passegue E, Wagner EF: AP-1 in mouse development and tumorigenesis. Oncogene 20:2401-2412, 2001.
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.
Johnson RS, Van Lingen B, Papaioannou VE, Spiegelman BM: A null mutation at the c-jun locus causes embryonic lethality and retarded cell growth in culture. Genes Dev 7:1309-1317, 1993.
Jonat C, Rahmsdorf HJ, Park KK, Cato AC, 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.
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.
Karin M, Liu Z, Zandi E: AP-1 function and regulation. Curr Opin Cell Biol 9:240-246, 1997.
Kolbus A, Herr I, Schreiber M et al.: C-Jundependent CD95-L expression is a ratelimiting step in the induction of apoptosis by alkylating agents. Mol Cell Biol 20:575-582, 2000.
Kouzarides T, Ziff E: Leucine zippers of fos, jun and GCN4 dictate dimerization specificity and thereby control DNA binding. Nature 340:568-571, 1989.
Leaner VD, Kinoshita I, Birrer MJ: AP-1 complexes containing cJun and JunB cause cellular transformation of Rat1a fibroblasts and share transcriptional targets. Oncogene 22:5619-5629, 2003.
Lee W, Mitchell P, Tjian R: Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell 49:741-52, 1987.
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.
Lloyd A, Yancheva N, Wasylyk B: Transformation suppressor activity of a Jun transcription factor lacking its activation domain. Nature 352:635-638, 1991.
Ludes-Meyers JH, Liu Y, Munoz-Medellin D et al.: AP-1 blockade inhibits the growth of normal and malignant breast cells. Oncogene 20:2771-2780, 2001.
Macian F, Lopez-Rodriguez C, Rao A: Partners in transcription: NFAT and AP-1. Oncogene 20:2476-2489, 2001.
MacLaren A, Clark W, Black EJ et al.: v-Jun stimulates both cdk2 kinase activity and G1/S progression via transcriptional repression of p21 CIP1. Oncogene 22:2383-2395, 2003.
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.
Marshall GM, Vanhamme L, Wong WY, Su H, Vogt PK: Wounding acts as a tumor promoter in chickens inoculated with avian sarcoma virus 17. Virology 188:373-377, 1992.
Marshall GM, Vanhamme L: Characterization of sarcoma cell lines from v-jun transgenic mice. Cancer Res 53:622-626, 1993.
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.
Nead MA, Baglia LA, Antinore MJ, Ludlow JW, McCance DJ: Rb binds c-Jun and activates transcription. EMBO J 17:2342-2352, 1998.
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.
Nishimura T, Vogt PK: The avian cellular homolog of the oncogene jun. Oncogene 3:659-663, 1988.
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.
Passegue E, Wagner EF: JunB suppresses cell proliferation by transcriptional activation of p16(INK4a) expression. EMBO J 19:2969-2979, 2000.
Pfarr CM, Mechta F, Spyrou G et al.: Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras. Cell 76:747-60, 1994.
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.
Qiao L, Han SI, 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.
Rahmsdorf HJ: Jun: transcription factor and oncoprotein. J Mol Med 74:725-747, 1996.
Raitano AB, Halpern JR, Hambuch TM, Sawyers CL: The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation. Proc Natl Acad Sci USA 92:11746-11750, 1995.
Rangatia J, Vangala RK, Singh SM et al.: c-Jun expression in acute myeloid leukemias inhibits C/EBPalpha DNA binding via leucine zipper domain interaction. Oncogene 22:4760-4764, 2003.
Ricci R, Eriksson U, Oudit GY et al.: Distinct functions of junD in cardiac hypertrophy and heart failure. Genes Dev 19:208-213, 2005.
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.
Roffler-Tarlov S, Brown JJ, Tarlov E et al.: Programmed cell death in the absence of c-Fos and c-Jun. Development 122:1-9, 1996.
Rossant J: Mouse mutants and cardiac development: new molecular insights into cardiogenesis. Circ Res 78:349-353, 1996.
Schorpp-Kistner M, Wang ZQ, Angel P, Wagner EF: JunB is essential for mammalian placentation. EMBO J 18:934-948, 1999.
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.
Schuh AC, Keating SJ, Monteclaro FS et al.: Obligatory wounding requirement for tumorigenesis in v-jun transgenic mice. Nature 346:756-760, 1990.
Schule R, Rangarajan P, Kliewer S et al.: Functional antagonism between oncoprotein c-Jun and the glucocorticoid receptor. Cell 62:217-226, 1990.
Schutte J, Minna JD, Birrer MJ: 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 USA 86:2257-2261, 1989.
Sevcikova S, Soucek 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.
Shaulian E, Karin M: AP-1 in cell proliferation and survival. Oncogene 20:2390-2400, 2001.
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.
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.
Smeal T, Binetruy B, Mercola DA et al.: Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature 354:494-496, 1991.
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.
Szabo E, Riffe ME, Steinberg SM, Birrer MJ, Linnoila RI: Altered cJUN expression: an early event in human lung carcinogenesis. Cancer Res 56:305-315, 1996.
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.
Thepot D, Weitzman JB, Barra J et al.: Targeted disruption of the murine junD gene results in multiple defects in male reproductive function. Development 127:143-153, 2000.
Tsai E, Yie J, Thanos D, Goldfeld AE: 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.
Wang ZQ, Liang J, Schellander K et al.: c-fosinduced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos. Cancer Res 55:6244-6251, 1995.
Watts RG, Ben-Ari ET, Bernstein LR 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.
Weitzman JB, Fiette L, Matsuo K, Yaniv M: JunD protects cells from p53-dependent senescence and apoptosis. Mol Cell 6:1109-1119, 2000.
Wiggan O, Hamel PA: Pax3 regulates morphogenetic cell behavior in vitro coincident with activation of a PCP/noncanonical Wnt-signalling cascade. J Cell Sci 115:531-541, 2002.
Wilkinson DG, Bhatt S, Ryseck RP, Bravo R: Tissue-specific expression of c-jun and junB during organogenesis in the mouse. Development 106:465-471, 1989.
Yang L, Kim HT, Munoz-Medellin D et al.: Induction of retinoid resistance in breast cancer cells by overexpression of cJun. Cancer Res 57:4652-4661, 1997.
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.
Young MR, Li JJ, Rincon M et al.: Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci USA 96:9827-9832, 1999.
Zhou F, Thompson EB: Role of c-jun induction in the glucocorticoid-evoked apoptotic pathway in human leukemic lymphoblasts. Mol Endocrinol 10:306-316, 1996.
Pazos E, Jimenez-Balsa A, Mascarenas JL, Vazquez ME. Sensing coiled-coil proteins through conformational modulation of energy transfer processes - selective detection of the oncogenic transcription factor c-Jun. Chem Sci. 2: 1984-1987, 2011.