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 Paper
  • Published:

Induction of p21Waf1/Cip1 by TNFα requires NF-κB activity and antagonizes apoptosis in Ewing tumor cells

Oncogene volume 19, pages 61–68 (2000)Cite this article

Abstract

The Ewing family of tumors is characterized by recurrent reciprocal translocations that generate chimeric proteins, either EWS–FLI-1 or EWS–ERG. These proteins are potent transcriptional activators and are responsible for maintaining the oncogenic properties of tumor cells. Since apoptosis appears to be the main mechanism whereby chemotherapy and radiation kill tumor cells, identification of events that can antagonize apoptosis in Ewing tumors is essential for improving their response to conventional therapies. Here, we report that the transcriptional factor NF-κB is a survival factor for Ewing tumor-derived cells. In fact, inhibition of NF-κB activation as a consequence of the overexpression of a degradation-resistant form of IκBα, IκBα (A32/36), sensitized these cells to TNFα-induced killing. Although treatment with TNFα did not modify the cellular expression of Bcl-2, c-IAP1, c-IAP2, p53 and EWS–FLI-1 proteins, it increased p21Waf1/Cip1 levels. This induction required NF-κB activation since it was not observed in the IκBα (A32/36) expressing cells. Moreover, overexpression of p21Waf1/Cip1 in these IκBα (A32/36)-expressing cells, in which NF-κB and consequently p21Waf1/Cip1 are no longer inducible by TNFα, decreased their susceptibility to TNFα-induced killing. Our results therefore identify p21Waf1/Cip1 as a mediator of the antiapoptotic effect of TNFα-induced NF-κB in Ewing tumor cells.

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

Similar content being viewed by others

References

  • Arsura M, Wu M and Sonenshein GE . 1996 Immunity 5: 31–40.

  • Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumoro K and Mizutani S . 1999 EMBO J 18: 1223–1234.

  • Baeuerle PA and Henkel T . 1994 Annu Rev Immunol 12: 141–179.

  • Baeuerle PA and Baltimore D . 1996 Cell 87: 13–20.

  • Bailly RA, Bosselut R, Zucman J, Cormier F, Delattre O, Roussel M, Thomas G and Ghysdael J . 1994 Mol Cell Biol 14: 3230–3241.

  • Baldwin AS, Jr . 1996 Annu Rev Immunol 14: 649–681.

  • Beg AA and Baltimore D . 1996 Science 274: 782–784.

  • Bertrand F, Atfi A, Cadoret A, L'Allemain G, Robin H, Lascols O, Capeau J and Cherqui G . 1998 J Biol Chem 273: 2931–2938.

  • Besançon F, Atfi A, Gespach C, Cayre YE and Bourgeade MF . 1998 Proc Nat Acad Sci USA 95: 8081–8086.

  • Brach MA, Hass R, Sherman ML, Gunji H, Weichselbaum R and Kufe D . 1991 J Clin Invest 88: 691–695.

  • Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T and Hannon GJ . 1995 Nature 377: 552–557.

  • Cai Z, Kôrner M, Tarantino N and Chouaib S . 1997 J Biol Chem 272: 96–101.

  • Cheng B, Christakos S and Mattson MP . 1994 Neuron 12: 139–153.

  • Das KC and White CW . 1997 J Biol Chem 272: 14914–14920.

  • Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Kovar H, Joubert I, de Jong P, Rouleau G, Aurias A and Thomas G . 1992 Nature 359: 162–165.

  • DeLuca C, Kwon HJ, Pelletier N, Wainberg MA and Hiscott J . 1998 Virology 244: 27–38.

  • Fisher DE . 1994 Cell 73: 539–542.

  • Gartel AL and Tyner AL . 1999 Exp Cell Res 246: 280–289.

  • Gorospe M, Wang X, Guyton KZ and Holbrook NJ . 1996 Mol Cell Biol 16: 6654–6660.

  • Gorospe M, Cirielli C, Wang X, Seth P, Capogrossi MC and Holbrook NJ . 1997 Oncogene 14: 929–935.

  • Green DR . 1998 Cell 94: 695–696.

  • Grilli M, Pizzi M, Memo M and Spano P . 1996 Science 274: 1383–1385.

  • Grilli M and Memo M . 1999 Cell Death Diff 6: 22–27.

  • Horowitz ME, Malawer MM, Woo SY and Hicks MJ . 1997 Principles and Practice of Pediatric Oncology Pizzo PA and Poplack DG eds Lippincott-Raven Philadelphia pp 831–864

    Google Scholar 

  • Jäättelä M . 1999 Exp Cell Res 248: 30–43.

  • Jiang Y and Porter AG . 1998 Biochem Biophys Res Comm 245: pp 691–697

  • Kovar H, Aryee DNT, Jug G, Henöckl C, Schemper M, Delattre O, Thomas G and Gadner H . 1996 Cell Growth Diff 7: 429–437.

  • Lipinski M, Braham K, Philip I, Wiels J, Philip T, Goridis C, Lenoir GM and Tursz T . 1987 Cancer Res 47: 183–187.

  • Liu Z, Hsu H, Goeddel DV and Karin M . 1996 Cell 87: 565–576.

  • Lu Y, Yamagishi N, Yagi T and Takebe H . 1998 Oncogene 16: 705–712.

  • Maniatis T . 1997 Science 278: 818–819.

  • May WA, Lessnick SL, Braun BS, Klemsz M, Lewis BC, Lunsford LB, Hromas R and Denny CT . 1993a Mol Cell Biol 13: 7393–7398.

  • May WA, Gishizky ML, Lessnick SL, Lunsford LB, Lewis BC, Delattre O, Zucman J, Thomas G and Denny CT . 1993b Proc Nat Acad Sci USA 90: 5752–5756.

  • Melot T, Gruel N, Doubeikovski A, Sevenet N, Teillaud JL and Delattre O . 1997 Hybridoma 16: 457–464.

  • Munoz E, Courtois G, Veschambre P, Jalinot P and Israel A . 1994 J Virol 68: 8035–8044.

  • Noguera R, Triche TJ, Navarro S, Tsokos M and Llombart-Bosch A . 1992 Lab Invest 66: 143–151.

  • Ohno T, Rao VN and Reddy ES . 1993 Cancer Res 53: 5859–5863.

  • O'Regan S, Diebler MF, Meunier FM and Vyas S . 1995 J Neurochem 64: 69–76.

  • Ouchida M, Ohno T, Fujimura Y, Rao VN and Reddy ESP . 1995 Oncogene 11: 1049–1054.

  • Polyak K, Waldman T, He TC, Kinzler KW and Vogelstein B . 1996 Genes Dev 10: 1945–1952.

  • Shim J, Lee H, Park J, Kim H and Choi EJ . 1996 Nature 381: 804–807.

  • Sorensen PHB, Lessnick SL, Lopez-Terrada D, Liu XF, Triche TJ and Denny CT . 1994 Nat Genet 6: 146–151.

  • Stancovski I and Baltimore D . 1997 Cell 91: 299–302.

  • Suzuki A, Tsutomi Y, Akahane K, Araki T and Miura M . 1998 Oncogene 17: 931–939.

  • Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S and Bauerle PA . 1995 EMBO J 14: 2876–2883.

  • Tanaka K, Iwakuma T, Harimaya K, Sato H and Iwamoto Y . 1997 J Clin Invest 99: 239–247.

  • Van Antwerp DJ, Martin SJ, Kafri T, Green DR and Verma IM . 1996 Science 274: 787–789.

  • Verma IM, Stevenson JK, Schwaetz EM, Van Antwerp D and Miyamoto S . 1995 Genes Dev 9: 2723–2735.

  • Wang CY, Mayo MW and Baldwin Jr AS . 1996 Science 274: 784–787.

  • Wang CY, Mayo MW, Korneluk RG, Goeddel DV and Baldwin Jr AS . 1998 Science 281: 1680–1683.

  • Wang CY, Cusack Jr JC, Liu R and Baldwin Jr AS . 1999a Nature Med 5: 412–417.

  • Wang Y, Blandino G and Givol D . 1999b Oncogene 18: 2643–2649.

  • Wang YA, Elson A and Leder P . 1997 Proc Nat Acad Sci USA 94: 14590–14595.

  • Whiteside ST, Epinat J, Rice NR and Israel A . 1997 EMBO J 16: 1413–1426.

  • Yi H, Fujimura Y, Ouchida M, Prasad DDK, Rao VN and Reddy ESP . 1997 Oncogene 14: 1259–1268.

  • Zong WX, Edelstein LC, Chen C, Bash J and Gelinas C . 1999 Genes Dev 13: 382–387.

  • Zucman J, Delattre O, Desmaze C, Epstein A, Stenman G, Speleman F, Fletchers CDM, Aurias A and Thomas G . 1993 Nat Genet 4: 341–345.

Download references

Acknowledgements

We thank Prof G Lenoir for providing the Ewing cell lines, Drs P A Baeuerle and M Korner for the IκBα(A32/36) mutant, A Israel for the (Igκ)3 plasmid and B Vogelstein for the p21Waf1/Cip1 encoding vector. We are grateful to Dr H Ankel for editing assistance and to J Sanceau for her generous help. We also thank C. Silvestri for skilful technical assistance and D Rouillard for FACS analysis. This work was supported by Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche sur le Cancer and the Ligue Nationale contre le Cancer.

Author information

Authors and Affiliations

  1. INSERM U365, Institut Curie, 26 rue d'Ulm, Paris, 75005, France

    Delphine Javelaud, Juana Wietzerbin & Françoise Besançon

  2. INSERM U 509, Institut Curie, 26 rue d'Ulm, Paris, 75005, France

    Olivier Delattre

Authors
  1. Delphine Javelaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Juana Wietzerbin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olivier Delattre
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Françoise Besançon
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Javelaud, D., Wietzerbin, J., Delattre, O. et al. Induction of p21Waf1/Cip1 by TNFα requires NF-κB activity and antagonizes apoptosis in Ewing tumor cells. Oncogene 19, 61–68 (2000). https://doi.org/10.1038/sj.onc.1203246

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203246

Keywords

This article is cited by

Search

Advanced search

Quick links