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:

p53 upregulates cFLIP, inhibits transcription of NF-κB-regulated genes and induces caspase-8-independent cell death in DLD-1 cells

Oncogene volume 20, pages 571–580 (2001)Cite this article

Abstract

One of the main functions of the tumor suppressor p53 is the induction of programmed cell death. Here we investigated in detail the molecular mechanisms that underlay p53 transactivation-dependent apoptosis in the human colon cancer cell line DLD-1. Although p53 upregulated the death receptors Fas, TRAIL-R1 and TRAIL-R2 in this cell line, p53-induced cell death occurred without detectable caspase-8 activation whereas, activation of caspase-9 and caspase-3 was readily observed. In addition to the upregulation of death receptors, p53 induced the pro-apoptotic Bcl-2 family members Bik and Bak and downregulated the anti-apoptotic Bcl-xL protein. Moreover, in RNase protection assay analyses as well as in reporter gene analyses we found a p53-dependent upregulation of the death receptor-inhibitory protein cFLIP. Together, these data argue for a p53-mediated activation of the mitochondrial pathway of apoptosis. In contrast to recently published data obtained in different cellular systems, there was no evidence for an essential role of NF-κB in p53-induced cell death. Moreover, induction of p53 interfered with TNF-induced NF-κB activation independently from apoptosis-induction.

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

Abbreviations

EMSA:

Electrophoretic mobility shift assay

FLIP:

FLICE-inhibitory protein

RPA:

RNase protectin assay

NF-κB:

nuclear factor κB

TRAIL-R1/2:

TNF-related apoptosis-inducing ligand (TRAIL) receptor 1/2

TNF:

tumor necrosis factor

References

  • Bennett M, MacDonald K, Chan SW, Luzio JP, Simari R and Weissberg P. . 1998 Science 282: 290–293.

  • Benoit V, Hellin AC, Huygen S, Gielen J, Bours V and Merville MP. . 2000 Oncogene 19: 4787–4794.

  • Caelles C, Helmberg A and Karin M. . 1994 Nature 370: 220–223.

  • Dignam JD, Lebovitz RM and Roeder RG. . 1983 Nucleic Acids Res. 11: 1475–1489.

  • Djerbi M, Screpanti V, Catrina Al, Bogen B, Biberfeld P and Grandien A. . 1999 J. Exp. Med. 190: 1025–1032.

  • El Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B. . 1993 Cell 75: 817–825.

  • Goltsev YV, Kovalenko AV, Arnold E, Varfolomeev EE, Brodianskii VM and Wallach D. . 1997 J. Biol. Chem. 272: 19641–19644.

  • Han DK, Chaudhary PM, Wright ME, Friedman C, Trask BJ, Riedel RT, Baskin DG, Schwartz SM and Hood L. . 1997 Proc. Natl. Acad. Sci. USA 94: 11333–11338.

  • Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ. . 1993 Cell 75: 805–816.

  • Haupt Y, Rowan S, Shaulian E, Vousden KH and Oren M. . 1995 Genes Dev. 9: 2170–2183.

  • Hu S, Vincenz C, Ni J, Gentz R and Dixit VM. . 1997 J. Biol. Chem. 272: 17255–17257.

  • Inohara N, Koseki T, Hu Y, Chen S and Nunez G. . 1997 Proc. Natl. Acad. Sci. USA 94: 10717–10722.

  • Irmler M, Steiner V, Ruegg C, Wajant H and Tschopp J. . 2000 FEBS Lett. 468: 129–133.

  • Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE and Tschopp J. . 1997 Nature 388: 190–195.

  • Levine AJ. . 1997 Cell 88: 323–331.

  • Levkau B, Scatena M, Giachelli CM, Ross R and Raines EW. . 1999 Nat. Cell Biol. 1: 227–233.

  • Lin Y, Devin A, Rodriguez Y and Liu ZG. . 1999 Genes Dev. 13: 2514–2526.

  • Medema JP, de Jong J, van Hall T, Melief CJ and Offringa R. . 1999 J. Exp. Med. 190: 1033–1038.

  • Miyashita T and Reed JC. . 1995 Cell 80: 293–299.

  • Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M, Friedman SL, Galle PR, Stremmel W, Oren M and Krammer PH. . 1998 J. Exp. Med. 188: 2033–2045.

  • Owen-Schaub LB, Zhang W, Cusack JC, Angelo LS, Santee SM, Fujiwara T, Roth JA, Deisseroth AB, Zhang WW and Kruzel E. . 1995 Mol. Cell Biol. 15: 3032–3040.

  • Pise-Masison CA, Mahieux R, Jiang H, Ashcroft M, Radonovich M, Duvall J, Guillerm C and Brady JN. . 2000 Mol. Cell Biol. 20: 3377–3386.

  • Rasper DM, Vaillancourt JP, Hadano S, Houtzager VM, Seiden I, Keen SL, Tawa P, Xanthoudakis S, Nasir J, Martindale D, Koop BF, Peterson EP, Thornberry NA, Huang J, MacPherson DP, Black SC, Hornung F, Lenardo MJ, Hayden MR, Roy S and Nicholson DW. . 1998 Cell Death Differ. 5: 271–288.

  • Reinke V and Lozano G. . 1997 Oncogene 15: 1527–1534.

  • Reuther JY and Baldwin Jr AS. . 1999 J. Biol. Chem. 274: 20664–20670.

  • Rodrigues NR, Rowan A, Smith MEF, Kerr IB, Bodmer WF, Gannon JV and Lane DP. . 1990 Proc. Natl. Acad. Sci. USA 87: 7555–7559.

  • Ryan KM, Ernst MK, Rice NR and Vousden KH. . 2000 Nature 404: 892–897.

  • Shao J, Fujiwara T, Kadowaki Y, Fukazawa T, Waku T, Itoshima T, Yamatsuji T, Nishizaki M, Roth JA and Tanaka N. . 2000 Oncogene 19: 726–736.

  • Sherr CJ and Weber JD. . 2000 Curr. Opin. Genet. Dev. 10: 94–99.

  • Shu HB, Halpin DR and Goeddel DV. . 1997 Immunity. 6: 751–763.

  • Slebos RJ, Lee MH, Plunkett BS, Kessis TD, Williams BO, Jacks T, Hedrick L, Kastan MB and Cho KR. . 1994 Proc. Natl. Acad. Sci. USA 91: 5320–5324.

  • Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, Fernandes-Alnemri T, Croce CM, Litwack G, Tomaselli KJ, Armstrong RC and Alnemri ES. . 1997 J. Biol. Chem. 272: 18542–18545.

  • Uberti D, Grilli M and Memo M. . 2000 Amino Acids 19: 253–261.

  • Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P and Wallach D. . 1998 Immunity. 9: 267–276.

  • Wagner AJ, Kokontis JM and Hay N. . 1994 Genes Dev. 8: 2817–2830.

  • Webster GA and Perkins ND. . 1999 Mol. Cell Biol. 19: 3485–3495.

  • Wu GS, Burns TF, McDonald III ER, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G and El Deiry WS. . 1997 Nat. Genet. 17: 141–143.

  • Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R and Beach D. . 1993 Nature 366: 701–704.

  • Yan Y, Shay JW, Wright WE and Mumby MC. . 1997 J. Biol. Chem. 272: 15220–15226.

  • Yu J, Zhang L, Hwang PM, Rago C, Kinzler KW and Vogelstein B. . 1999 Proc. Natl. Acad. Sci. USA 96: 14517–14522.

  • Zhao R, Gish K, Murphy M, Yin Y, Notterman D, Hoffman WH, Tom E, Mack DH and Levine AJ. . 2000 Genes Dev. 14: 981–993.

Download references

Acknowledgements

The authors wish to thank Bert Vogelstein, John Hopkins Oncology Center, Baltimore, USA for the p53-inducible DLD-1 cell lines and Evelyne May, Laboratoire de Cancérogenèse moléculaire, France, for supplying us with expression plasmids for p53. We also thank Peter Krammer (German Cancer Research Center, Heidelberg, Germany) and Klaus Schulze-Oshoff (University of Tübingen, Germany) for kindly providing us with mAbs against cFLIP and caspase-8, respectively. Recombinant FasL and TRAIL were a kind gift from Pascal Schneider and Jürg Tschopp (University of Lausanne, Switzerland). This work was supported by Deutsche Forschungsgemeinschaft Grant Wa 1025/3-1 and Sonderforschungsbereich 495 project A5.

Author information

Authors and Affiliations

  1. Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, Stuttgart, 70569, Germany

    Till Bartke, Daniela Siegmund, Nathalie Peters, Monica Reichwein, Frank Henkler, Peter Scheurich & Harald Wajant

Authors
  1. Till Bartke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniela Siegmund
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nathalie Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Monica Reichwein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frank Henkler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Scheurich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Harald Wajant
    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

Bartke, T., Siegmund, D., Peters, N. et al. p53 upregulates cFLIP, inhibits transcription of NF-κB-regulated genes and induces caspase-8-independent cell death in DLD-1 cells. Oncogene 20, 571–580 (2001). https://doi.org/10.1038/sj.onc.1204124

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204124

Keywords

This article is cited by

Search

Advanced search

Quick links