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Cell transformation by v-Rel reveals distinct roles of AP-1 family members in Rel/NF-κB oncogenesis

Oncogene volume 29, pages 4925–4937 (2010)Cite this article

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Abstract

Cell transformation by the v-rel oncogene is mediated by the aberrant expression of genes that are normally tightly regulated by other Rel/NF-κB family members. Although a number of genes inappropriately activated or suppressed by v-Rel have been identified, their contributions to the v-Rel transformation process have been poorly characterized. Here, we examine the role of individual AP-1 proteins in v-Rel-mediated transformation. v-Rel-transformed cells exhibit elevated RNA and protein expression of c-Fos, c-Jun and ATF2 and sustained repression of Fra-2. c-Fos and c-Jun are essential in both the initiation and maintenance of v-Rel-mediated transformation, whereas Fra-2 is dispensable. By employing a c-Jun dimerization mutant, we further identified Fos/Jun heterodimers as major contributors to the v-Rel transformation process. The inability of c-Rel to induce the expression of c-Fos and c-Jun contributes to its weaker oncogenic potential relative to v-Rel. Our studies also demonstrate that v-Rel may induce AP-1 members by directly upregulating gene expression (c-fos and ATF2) and by activating pathways that stimulate AP-1 activity. Although elevated expression of ATF2 is also required for v-Rel-mediated transformation, its ectopic overexpression is inhibitory. Investigating the mode of ATF2 regulation revealed a positive feedback mechanism whereby ATF2 induces p38 MAPK phosphorylation to further induce its own activity. In addition, these studies identified Ha-Ras as an effector of v-Rel-mediated transformation and reveal a novel role for ATF2 in the inhibition of the Ras–Raf–MEK–ERK signaling pathway. Overall, these studies reveal distinct and complex roles of AP-1 proteins in Rel/NF-κB oncogenesis.

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References

  • Aggarwal BB . (2004). Nuclear factor-κB: the enemy within. Cancer Cell 6: 203–208.

    Article  CAS  Google Scholar 

  • Angel P, Hattori K, Smeal T, Karin M . (1988). The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell 55: 875–885.

    Article  CAS  Google Scholar 

  • Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ et al. (1987). Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49: 729–739.

    Article  CAS  Google Scholar 

  • Bhoumik A, Fichtman B, Derossi C, Breitwieser W, Kluger HM, Davis S et al. (2008). Suppressor role of activating transcription factor 2 (ATF2) in skin cancer. Proc Natl Acad Sci USA 105: 1674–1679.

    Article  CAS  Google Scholar 

  • Bonizzi G, Karin M . (2004). The two NF-κB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25: 280–288.

    Article  CAS  Google Scholar 

  • Breitwieser W, Lyons S, Flenniken AM, Ashton G, Bruder G, Willington M et al. (2007). Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells. Genes Dev 21: 2069–2082.

    Article  CAS  Google Scholar 

  • Chaudhary A, King WG, Mattaliano MD, Frost JA, Diaz B, Morrison DK et al. (2000). Phosphatidylinositol 3-kinase regulates Raf1 through Pak phosphorylation of serine 338. Curr Biol 10: 551–554.

    Article  CAS  Google Scholar 

  • Chen FE, Ghosh G . (1999). Regulation of DNA binding by Rel/NF-κB transcription factors: structural views. Oncogene 18: 6845–6852.

    Article  CAS  Google Scholar 

  • Chin M, Herscovitch M, Zhang N, Waxman DJ, Gilmore TD . (2009). Overexpression of an activated REL mutant enhances the transformed state of the human B-lymphoma BJAB cell line and alters its gene expression profile. Oncogene 28: 2100–2111.

    Article  CAS  Google Scholar 

  • Chong H, Lee J, Guan KL . (2001). Positive and negative regulation of Raf kinase activity and function by phosphorylation. EMBO J 20: 3716–3727.

    Article  CAS  Google Scholar 

  • Courtois G, Gilmore TD . (2006). Mutations in the NF-κB signaling pathway: implications for human disease. Oncogene 25: 6831–6843.

    Article  CAS  Google Scholar 

  • Das RM, Van Hateren NJ, Howell GR, Farrell ER, Bangs FK, Porteous VC et al. (2006). A robust system for RNA interference in the chicken using a modified microRNA operon. Dev Biol 294: 554–563.

    Article  CAS  Google Scholar 

  • Dyer RB, Herzog NK . (1995). Isolation of intact nuclei for nuclear extract preparation from a fragile B-lymphocyte cell line. Biotechniques 19: 192–195.

    CAS  PubMed  Google Scholar 

  • Ewert D, Duhadaway J . (1999). Inhibition of apoptosis by Marek′s disease viruses. Acta Virol 43: 133–135.

    CAS  PubMed  Google Scholar 

  • Fujii M, Minamino T, Nomura M, Miyamoto K, Tanaka J, Seiki M . (1997). v-Rel activates the proto-oncogene c-jun promoter: a correlation with its transforming activity. Leukemia 11 (Suppl 3): 402–404.

    PubMed  Google Scholar 

  • Fujioka S, Niu J, Schmidt C, Sclabas GM, Peng B, Uwagawa T et al. (2004). NF-κB and AP-1 connection: mechanism of NF-κB-dependent regulation of AP-1 activity. Mol Cell Biol 24: 7806–7819.

    Article  CAS  Google Scholar 

  • Gilmore TD . (1999). Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel. Oncogene 18: 6925–6937.

    Article  CAS  Google Scholar 

  • Hai T, Curran T . (1991). Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proc Natl Acad Sci USA 88: 3720–3724.

    Article  CAS  Google Scholar 

  • Hess J, Angel P, Schorpp-Kistner M . (2004). AP-1 subunits: quarrel and harmony among siblings. J Cell Sci 117: 5965–5973.

    Article  CAS  Google Scholar 

  • Howe LR, Marshall CJ . (1993). Identification of amino acids in p21ras involved in exchange factor interaction. Oncogene 8: 2583–2590.

    CAS  PubMed  Google Scholar 

  • Hrdlickova R, Nehyba J, Bose Jr HR. . (2001). Interferon regulatory factor 4 contributes to transformation of v-Rel-expressing fibroblasts. Mol Cell Biol 21: 6369–6386.

    Article  CAS  Google Scholar 

  • Hrdlickova R, Nehyba J, Humphries EH . (1994). v-Rel induces expression of three avian immunoregulatory surface receptors more efficiently than c-Rel. J Virol 68: 308–319.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kalaitzidis D, Davis RE, Rosenwald A, Staudt LM, Gilmore TD . (2002). The human B-cell lymphoma cell line RC-K8 has multiple genetic alterations that dysregulate the Rel/NF-κB signal transduction pathway. Oncogene 21: 8759–8768.

    Article  CAS  Google Scholar 

  • Karin M, Liu Z, Zandi E . (1997). AP-1 function and regulation. Curr Opin Cell Biol 9: 240–246.

    Article  CAS  Google Scholar 

  • Kralova J, Liss AS, Bargmann W, Bose Jr HR . (1998). AP-1 factors play an important role in transformation induced by the v-rel oncogene. Mol Cell Biol 18: 2997–3009.

    Article  CAS  Google Scholar 

  • Lewis JS, Vijayanathan V, Thomas TJ, Pestell RG, Albanese C, Gallo MA et al. (2005). Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: a mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. Oncol Res 15: 113–128.

    Article  CAS  Google Scholar 

  • Liss AS, Bose HR . (2008). Encyclopedia of Virology In: Mahy BWJ and Van Regenmortel MHV (eds). pp 412–419.

  • Liss AS, Bose Jr HR . (2002). Mutational analysis of the v-Rel dimerization interface reveals a critical role for v-Rel homodimers in transformation. J Virol 76: 4928–4939.

    Article  CAS  Google Scholar 

  • Luo J, Manning BD, Cantley LC . (2003). Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4: 257–262.

    Article  CAS  Google Scholar 

  • Maekawa T, Shinagawa T, Sano Y, Sakuma T, Nomura S, Nagasaki K et al. (2007). Reduced levels of ATF-2 predispose mice to mammary tumors. Mol Cell Biol 27: 1730–1744.

    Article  CAS  Google Scholar 

  • Majid SM, Liss AS, You M, Bose HR . (2006). The suppression of SH3BGRL is important for v-Rel-mediated transformation. Oncogene 25: 756–768.

    Article  CAS  Google Scholar 

  • Mathas S, Hinz M, Anagnostopoulos I, Krappmann D, Lietz A, Jundt F et al. (2002). Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-κB. EMBO J 21: 4104–4113.

    Article  CAS  Google Scholar 

  • Mathas S, Johrens K, Joos S, Lietz A, Hummel F, Janz M et al. (2005). Elevated NF-κB p50 complex formation and Bcl-3 expression in classical Hodgkin, anaplastic large-cell, and other peripheral T-cell lymphomas. Blood 106: 4287–4293.

    Article  CAS  Google Scholar 

  • Minden A, Lin A, Claret FX, Abo A, Karin M . (1995). Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell 81: 1147–1157.

    Article  CAS  Google Scholar 

  • Morton S, Davis RJ, Cohen P . (2004). Signalling pathways involved in multisite phosphorylation of the transcription factor ATF-2. FEBS Lett 572: 177–183.

    Article  CAS  Google Scholar 

  • Nehyba J, Hrdlickova R, Bose Jr HR. . (1997). Differences in κB DNA-binding properties of v-Rel and c-Rel are the result of oncogenic mutations in three distinct functional regions of the Rel protein. Oncogene 14: 2881–2897.

    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 

  • Rayet B, Gelinas C . (1999). Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18: 6938–6947.

    Article  CAS  Google Scholar 

  • Ricote M, Garcia-Tunon I, Bethencourt F, Fraile B, Onsurbe P, Paniagua R et al. (2006). The p38 transduction pathway in prostatic neoplasia. J Pathol 208: 401–407.

    Article  CAS  Google Scholar 

  • Robbins DJ, Cheng M, Zhen E, Vanderbilt CA, Feig LA, Cobb MH . (1992). Evidence for a Ras-dependent extracellular signal-regulated protein kinase (ERK) cascade. Proc Natl Acad Sci USA 89: 6924–6928.

    Article  CAS  Google Scholar 

  • Shaulian E . (2010). AP-1 - The Jun proteins: Oncogenes or tumor suppressors in disguise? Cell Signal 22: 894–899.

    Article  CAS  Google Scholar 

  • Stephens RM, Rice NR, Hiebsch RR, Bose Jr HR., Gilden RV . (1983). Nucleotide sequence of v-rel: the oncogene of reticuloendotheliosis virus. Proc Natl Acad Sci USA 80: 6229–6233.

    Article  CAS  Google Scholar 

  • Sun H, King AJ, Diaz HB, Marshall MS . (2000). Regulation of the protein kinase Raf-1 by oncogenic Ras through phosphatidylinositol 3-kinase, Cdc42/Rac and Pak. Curr Biol 10: 281–284.

    Article  CAS  Google Scholar 

  • van Dam H, Castellazzi M . (2001). Distinct roles of Jun:Fos and Jun:ATF dimers in oncogenesis. Oncogene 20: 2453–2464.

    Article  CAS  Google Scholar 

  • Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V . (2008). The role of ATF-2 in oncogenesis. Bioessays 30: 314–327.

    Article  CAS  Google Scholar 

  • Zoumpourlis V, Papassava P, Linardopoulos S, Gillespie D, Balmain A, Pintzas A . (2000). High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model. Oncogene 19: 4011–4021.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Ashley Sims for her technical assistance and Marc Castellazzi for providing the Coll and Jun2 luciferase reporter vectors. This study was supported by Public Health Service Grants CA33192 and CA098151 from the National Cancer Institute.

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Author notes

  1. A S Liss

    Present address: Current address: Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Blossom St, Boston, MA 02114, USA.,

  2. J Kralova

    Present address: Current address: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic.,

  3. A S Liss and R Tiwari: These authors contributed equally to this work.

Authors and Affiliations

  1. Section of Molecular Genetics and Microbiology, Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA

    A S Liss, R Tiwari, J Kralova & H R Bose Jr

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  1. A S Liss
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Correspondence to H R Bose Jr.

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Liss, A., Tiwari, R., Kralova, J. et al. Cell transformation by v-Rel reveals distinct roles of AP-1 family members in Rel/NF-κB oncogenesis. Oncogene 29, 4925–4937 (2010). https://doi.org/10.1038/onc.2010.239

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