Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Targeting c-Jun and JunB proteins as potential anticancer cell therapy

Oncogene volume 27, pages 641–652 (2008)Cite this article

Abstract

The activating protein-1 transcription factor, in particular the Jun proteins play critical roles in the regulation of cell proliferation and tumor progression. To study the potential clinical relevance of interfering with JunB expression, we generated retroviruses expressing short hairpin RNA. Reduction of JunB levels causes increased proliferation and tumorigenicity in wild-type murine fibroblasts, whereas in c-Jun knockout cells p53-independent cell cycle arrest and apoptosis are induced. Using melanoma-derived B16-F10 cancer cells the combination of JunB knockdown and c-Jun/JNK inactivation leads to cell cycle arrest and apoptosis-inducing factor-dependent apoptosis. Furthermore, the combined treatment extends survival of mice inoculated with the tumor cells. These results indicate that in the absence of c-Jun, JunB can act as a tumor promoter and inactivation of both, c-Jun and JunB, could provide a valuable strategy for antitumor intervention.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Artus C, Maquarre E, Moubarak RS, Delettre C, Jasmin C, Susin SA et al. (2006). CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells. Oncogene 25: 5741–5751.

    Article  CAS  Google Scholar 

  • Bain J, McLauchlan H, Elliott M, Cohen P . (2003). The specificities of protein kinase inhibitors: an update. Biochem J 371: 199–204.

    Article  CAS  Google Scholar 

  • Bennett BL, Sasaki DT, Murray BW, O'Leary EC, Sakata ST, Xu W et al. (2001). SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 98: 13681–13686.

    Article  CAS  Google Scholar 

  • Bohmann D, Bos TJ, Admon A, Nishimura T, Vogt PK, Tjian R . (1987). Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1. Science 238: 1386–1392.

    Article  CAS  Google Scholar 

  • Bowden GT, Schneider B, Domann R, Kulesz-Martin M . (1994). Oncogene activation and tumor suppressor gene inactivation during multistage mouse skin carcinogenesis. Cancer Res 54: 1882s–1885s.

    CAS  PubMed  Google Scholar 

  • Brummelkamp TR, Bernards R, Agami R . (2002). Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2: 243–247.

    Article  CAS  Google Scholar 

  • Chiu R, Angel P, Karin M . (1989). Jun-B differs in its biological properties from, and is a negative regulator of, c-Jun. Cell 59: 979–986.

    Article  CAS  Google Scholar 

  • Choi BY, Choi HS, Ko K, Cho YY, Zhu F, Kang BS et al. (2005). The tumor suppressor p16(INK4a) prevents cell transformation through inhibition of c-Jun phosphorylation and AP-1 activity. Nat Struct Mol Biol 12: 699–707.

    Article  CAS  Google Scholar 

  • Curran T, Peters G, Van Beveren C, Teich NM, Verma IM . (1982). FBJ murine osteosarcoma virus: identification and molecular cloning of biologically active proviral DNA. J Virol 44: 674–682.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Curran T, Teich NM . (1982). Candidate product of the FBJ murine osteosarcoma virus oncogene: characterization of a 55,000-dalton phosphoprotein. J Virol 42: 114–122.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deng T, Karin M . (1993). JunB differs from c-Jun in its DNA-binding and dimerization domains, and represses c-Jun by formation of inactive heterodimers. Genes Dev 7: 479–490.

    Article  CAS  Google Scholar 

  • Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M et al. (2003). Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 112: 181–192.

    Article  CAS  Google Scholar 

  • Eferl R, Wagner EF . (2003). AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3: 859–868.

    Article  CAS  Google Scholar 

  • Ennis BW, Fultz KE, Smith KA, Westwick JK, Zhu D, Boluro-Ajayi M et al. (2005). Inhibition of tumor growth, angiogenesis, and tumor cell proliferation by a small molecule inhibitor of c-Jun N-terminal kinase. J Pharmacol Exp Ther 313: 325–332.

    Article  CAS  Google Scholar 

  • Galluzzi L, Larochette N, Zamzami N, Kroemer G . (2006). Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 25: 4812–4830.

    Article  CAS  Google Scholar 

  • Gururajan M, Chui R, Karuppannan AK, Ke J, Jennings CD, Bondada S . (2005). c-Jun N-terminal kinase (JNK) is required for survival and proliferation of B-lymphoma cells. Blood 106: 1382–1391.

    Article  CAS  Google Scholar 

  • Gurzov EN, Izquierdo M . (2006). RNA interference against Hec1 inhibits tumor growth in vivo. Gene Therapy 13: 1–7.

    Article  CAS  Google Scholar 

  • Joseloff E, Bowden GT . (1997). Regulation of the transcription factor AP-1 in benign and malignant mouse keratinocyte cells. Mol Carcinog 18: 26–36.

    Article  CAS  Google Scholar 

  • Kang YH, Yi MJ, Kim MJ, Park MT, Bae S, Kang CM et al. (2004). Caspase-independent cell death by arsenic trioxide in human cervical cancer cells: reactive oxygen species-mediated poly(ADP-ribose) polymerase-1 activation signals apoptosis-inducing factor release from mitochondria. Cancer Res 64: 8960–8967.

    Article  CAS  Google Scholar 

  • Libermann TA, Zerbini LF . (2006). Targeting transcription factors for cancer gene therapy. Curr Gene Ther 6: 17–33.

    Article  CAS  Google Scholar 

  • Lopez-Bergami P, Huang C, Goydos JS, Yip D, Bar-Eli M, Herlyn M et al. (2007). Rewired ERK-JNK signaling pathways in melanoma. Cancer Cell 11: 447–460.

    Article  CAS  Google Scholar 

  • Mao X, Orchard G, Lillington DM, Russell-Jones R, Young BD, Whittaker SJ . (2003). Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas. Blood 101: 1513–1519.

    Article  CAS  Google Scholar 

  • Marchetti P, Hirsch T, Zamzami N, Castedo M, Decaudin D, Susin SA et al. (1996). Mitochondrial permeability transition triggers lymphocyte apoptosis. J Immunol 157: 4830–4836.

    CAS  PubMed  Google Scholar 

  • Mariani O, Brennetot C, Coindre JM, Gruel N, Ganem C, Delattre O et al. (2007). JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas. Cancer Cell 11: 361–374.

    Article  CAS  Google Scholar 

  • Mingo-Sion AM, Marietta PM, Koller E, Wolf DM, Van Den Berg CL . (2004). Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells. Oncogene 23: 596–604.

    Article  CAS  Google Scholar 

  • Nateri AS, Spencer-Dene B, Behrens A . (2005). Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature 437: 281–285.

    Article  CAS  Google Scholar 

  • Passegue B, Jochum W, Schorpp-Kistner M, Mohle-Steinlein U, Wargger EF . (2001). Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking JunB expression in the myeloid lineage. Cell 104: 21–32.

    Article  CAS  Google Scholar 

  • Passegue E, Jochum W, Behrens A, Ricci R, Wagner EF . (2002). JunB can substitute for Jun in mouse development and cell proliferation. Nat Genet 30: 158–166.

    Article  CAS  Google Scholar 

  • Passegue E, Wagner EF, Weissman IL . (2004). JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119: 431–443.

    Article  CAS  Google Scholar 

  • Rassidakis GZ, Thomaides A, Atwell C, Ford R, Jones D, Claret FX et al. (2005). JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis. Mod Pathol 18: 1365–1370.

    Article  CAS  Google Scholar 

  • Rauscher III FJ, Sambucetti LC, Curran T, Distel RJ, Spiegelman BM . (1988). Common DNA binding site for Fos protein complexes and transcription factor AP-1. Cell 52: 471–480.

    Article  CAS  Google Scholar 

  • Schreiber M, Kolbus A, Piu F, Szabowski A, Mohle-Steinlein U, Tian J et al. (1999). Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev 13: 607–619.

    Article  CAS  Google Scholar 

  • Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM et al. (1999). Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397: 441–446.

    Article  CAS  Google Scholar 

  • Szremska AP, Kenner L, Weisz E, Ott RG, Passegue E, Artwohl M et al. (2003). JunB inhibits proliferation and transformation in B-lymphoid cells. Blood 102: 4159–4165.

    Article  CAS  Google Scholar 

  • Vleugel MM, Greijer AE, Bos R, van der Wall E, van Diest PJ . (2006). c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer. Hum Pathol 37: 668–674.

    Article  CAS  Google Scholar 

  • Vogt PK . (2002). Fortuitous convergences: the beginnings of JUN. Nat Rev Cancer 2: 465–469.

    Article  CAS  Google Scholar 

  • Xia HH, He H, Wang JD, Gu Q, Lin MC, Zou B et al. (2006). Induction of apoptosis and cell cycle arrest by a specific c-Jun NH(2)-terminal kinase (JNK) inhibitor, SP-600125, in gastrointestinal cancers. Cancer Lett 241: 268–274.

    Article  CAS  Google Scholar 

  • Yang MY, Liu TC, Chang JG, Lin PM, Lin SF . (2003). JunB gene expression is inactivated by methylation in chronic myeloid leukemia. Blood 101: 3205–3211.

    Article  CAS  Google Scholar 

  • Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ et al. (2002). Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297: 259–263.

    Article  CAS  Google Scholar 

  • Zenz R, Wagner EF . (2006). Jun signalling in the epidermis: from developmental defects to psoriasis and skin tumors. Int J Biochem Cell Biol 38: 1043–1049.

    Article  CAS  Google Scholar 

  • Zhang W, Hart J, McLeod HL, Wang HL . (2005). Differential expression of the AP-1 transcription factor family members in human colorectal epithelial and neuroendocrine neoplasms. Am J Clin Pathol 124: 11–19.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the ‘Fundación de investigación médica Mutua Madrileña Automovilística’ FMMA, Madrid, Spain. The Centro de Biología Molecular SO is the recipient of an institutional grant from the Ramón Areces Foundation and EN Gurzov was supported by a grant from the Comunidad Autónoma de Madrid-España. The IMP is funded by Boehringer Ingelheim.

Author information

Authors and Affiliations

  1. Department of Molecular Biology, Facultad de Ciencias, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain

    E N Gurzov, J M Alfaro & M Izquierdo

  2. Research Institute of Molecular Pathology (I.M.P.), Dr. Bohr-Gasse 7, Vienna, Austria

    L Bakiri & E F Wagner

Authors
  1. E N Gurzov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Bakiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J M Alfaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E F Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Izquierdo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Izquierdo.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gurzov, E., Bakiri, L., Alfaro, J. et al. Targeting c-Jun and JunB proteins as potential anticancer cell therapy. Oncogene 27, 641–652 (2008). https://doi.org/10.1038/sj.onc.1210690

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210690

Keywords

This article is cited by

Search

Advanced search

Quick links