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:

Tumour regression in a ligand inducible manner mediated by a chimeric tumour suppressor derived from p53

Oncogene volume 19, pages 337–350 (2000)Cite this article

Abstract

The p53 tumour suppressor induces cell cycle arrest and apoptosis in response to cellular stresses. p53 is inactivated by various cellular and viral factors. We set out to generate regulatable p53 derivatives that are highly inducible by synthetic ligands, escape inactivation and efficiently induce apoptosis. We have generated Ligand Inducible Chimeric Tumour Suppressors (LI-CTS), that are inactive unless provided with artificial ligands. They are resistant to inactivation, due to the replacement of domains that mediate p53 inhibition by heterologous sequences. LI-CTS are activated by micro-molar concentrations of ligand in a variety of cell lines. Following ligand addition, they translocate to the nucleus, activate p53 inducible genes and induce apoptosis. We have established human head and neck squamous cell carcinoma lines that stably express LI-CTS, which are inducible. These lines form tumours in nude mice in the absence of ligand. Addition of ligand inhibits tumour formation, and moreover, regresses established tumours by apoptosis. Although regulatable p53 expression has been achieved previously, our study provides the first demonstration of regulatable in vivo regression of tumours in a p53 based approach. Regulated inhibition and regression of tumours with a ligand inducible chimeric tumour suppressor could provide a novel approach to p53 based gene therapy.

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

References

  • Akli S, Caillaud C, Vigne E, Stratford-Perricaudet LD, Poenaru L, Perricaudet M, Kahn A and Peschanski MR. . 1993 Nat. Genet. 3: 224–228.

  • Ali S, Metzger D, Bornert JM and Chambon P. . 1993 EMBO J. 12: 1153–1160.

  • Attardi LD, Lowe SW, Brugarolas J and Jacks T. . 1996 EMBO J. 15: 3693–3701.

  • Bakin AV and Curran T. . 1999 Science 283: 387–390.

  • Baniahmad A, Leng X, Burris TP, Tsai SY, Tsai MJ and O'Malley BW. . 1995 Mol. Cell Biol. 15: 76–86.

  • Bates, S. & Vousden, K.H. . 1996 Curr. Opin. Genet. Dev. 6: 12–18

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

  • Bond J, Haughton M, Blaydes J, Gire V, Wynford-Thomas D and Wyllie F. . 1996 Oncogene 13: 2097–2104.

  • Bossy-Wetzel E, Bakiri L and Yaniv M. . 1997 EMBO J. 16: 1695–1709.

  • Bottger A, Bottger V, Sparks A, Liu WL, Howard SF and Lane DP. . 1997 Curr. Biol. 7: 860–869.

  • Brachmann RK, Yu K, Eby Y, Pavletich NP and Boeke JD. . 1998 EMBO J. 17: 1847–1859.

  • Brou C, Chaudhary S, Davidson I, Lutz Y, Wu J, Egly JM, Tora L and Chambon P. . 1993 EMBO J. 12: 489–499.

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

  • Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR and Kley N. . 1995 Nature 377: 646–649.

  • Burcin MM, Schiedner G, Kochanek S, Tsai SY and O'Malley BW. . 1999 Proc. Natl. Acad. Sci. USA 96: 355–360.

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

  • Casanova J, Helmer E, Selmi-Ruby S, Qi JS, Au-Fliegner M, Desai-Yajnik V, Koudinova N, Yarm F, Raaka BM and Samuels HH. . 1994 Mol. Cell. Biol. 14: 5756–5765.

  • Chen C and Okayama H. . 1987 Mol. Cell. Biol. 7: 2745–2752.

  • Chen J, Marechal V and Levine AJ. . 1993 Mol. Cell. Biol. 13: 4107–4114.

  • Choi J and Donehower LA. . 1999 Cell. Mol. Life Sci. 55: 38–47.

  • Coll JL, Negoescu A, Louis N, Sachs L, Tenaud C, Girardot V, Demeinex B, Brambilla E, Brambilla C and Favrot M. . 1998 Hum. Gene Ther. 9: 2063–2074.

  • Conseiller E, Debussche L, Landais D, Venot C, Maratrat M, Sierra V, Tocque B and Bracco L. . 1998 J. Clin. Invest. 101: 120–127.

  • Danielian PS, White R, Hoare SA, Fawell SE and Parker MG. . 1993 Mol. Endocrinol. 7: 232–240.

  • Davidson BL, Allen ED, Kozarsky KF, Wilson JM and Roessler BJ. . 1993 Nat. Genet. 3: 219–223.

  • Deng C, Zhang P, Harper JW, Elledge SJ and Leder P. . 1995 Cell 82: 675–684.

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS and Bradley A. . 1992 Nature 356: 215–221.

  • 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.

  • Eldadah BA, Yakovlev AG and Faden AI. . 1996 Nucleic. Acids Res. 24: 4092–4093.

  • Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D and Chambon P. . 1996 Proc. Natl. Acad. Sci. USA 93: 10887–10890.

  • Feil R, Wagner J, Metzger D and Chambon P. . 1997 Biochem. Biophys. Res. Commun. 237: 752–757.

  • Ford LG and Johnson KA. . 1997 Prog. Clin. Biol. Res. 396: 271–282.

  • Freedman DA and Levine AJ. . 1998 Mol. Cell. Biol. 18: 7288–7293.

  • Friedlander P, Haupt Y, Prives C and Oren M. . 1996 Mol. Cell. Biol. 16: 4961–4971.

  • Funk WD, Pak DT, Karas RH, Wright WE and Shay JW. . 1992 Mol. Cell. Biol. 12: 2866–2871.

  • Gallardo D, Drazan KE and McBride WH. . 1996 Cancer Res. 56: 4891–4893.

  • Giaccia AJ and Kastan MB. . 1998 Genes Dev. 12: 2973–2983.

  • Gomez-Manzano C, Fueyo J, Kyritsis AP, Steck PA, Roth JA, McDonnell TJ, Steck KD, Levin VA and Yung WK. . 1996 Cancer Res. 56: 694–699.

  • Gradishar WJ and Jordan VC. . 1997 J. Clin. Oncol. 15: 840–852.

  • Haupt Y, Maya R, Kazaz A and Oren M. . 1997 Nature 387: 296–299.

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

  • Hinds PW, Finlay CA, Quartin RS, Baker SJ, Fearon ER, Vogelstein B and Levine AJ. . 1990 Cell Growth Differ. 1: 571–580.

  • Hollstein M, Sidransky D, Vogelstein B and Harris CC. . 1991 Science 253: 49–53.

  • Hsieh JK, Chan FS, O'Connor DJ, Mittnacht S, Zhong S and Lu X. . 1999 Mol. Cell. 3: 181–193.

  • Hupp TR, Sparks A and Lane DP. . 1995 Cell 83: 237–245.

  • Israeli D, Tessler E, Haupt Y, Elkeles A, Wilder S, Amson R, Teleman A and Oren M. . 1997 EMBO J. 16: 4384–4392.

  • Jiang D, Srinivasan A, Lozano G and Robbins PD. . 1993 Oncogene 8: 2805–2812.

  • Juven T, Barak Y, Zauberman A, George DL and Oren M. . 1993 Oncogene 8: 3411–3416.

  • Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE and Poirer GG. . 1993 Cancer Res. 53: 3976–3985.

  • Knudson CM, Tung KS, Tourtellotte WG, Brown GA and Korsmeyer SJ. . 1995 Science 270: 96–99.

  • Kubbutat MH, Jones SN and Vousden KH. . 1997 Nature 387: 299–303.

  • Lam EW and Watson RJ. . 1993 EMBO J. 12: 2705–2713.

  • Le Gal La Salle G, Robert JJ, Berrard S, Ridoux V, Stratford-Perricaudet LD, Perricaudet M and Mallet J. . 1993 Science 259: 988–990.

  • Liang SH, Hong D and Clarke MF. . 1998 J. Biol. Chem. 273: 19817–19821.

  • Liu TJ, Zhang WW, Taylor DL, Roth JA, Goepfert H and Clayman GL. . 1994 Cancer Res. 54: 3662–3667.

  • Malkin D, Li FP, Strong LC, Fraumeni Jr JF, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA et al. 1990 Science 250: 1233–1238.

  • McGowan AJ, Ruiz-Ruiz MC, Gorman AM, Lopez-Rivas A and Cotter TG. . 1996 FEBS Lett. 392: 299–303.

  • Milner J and Medcalf EA. . 1991 Cell 65: 765–774.

  • Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B and Reed JC. . 1994 Oncogene 9: 1799–1805.

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

  • Momand J, Jung D, Wilczynski S and Niland J. . 1998 Nucleic. Acids Res. 26: 3453–3459.

  • Momand J, Zambetti GP, Olson DC, George D and Levine AJ. . 1992 Cell 69: 1237–1245.

  • Momose F, Araida T, Negishi A, Ichijo H, Shioda S and Sasaki S. . 1989 Oral Pathol. Med. 18: 391–395.

  • Mukhopadhyay T and Roth JA. . 1998 Oncogene 17: 241–246.

  • Nemani M, Linares-Cruz G, Bruzzoni-Giovanelli H, Roperch JP, Tuynder M, Bougueleret L, Cherif D, Medhioub M, Pasturaud P, Alvaro V, der Sarkissan H, Cazes L, Le Paslier D, Le Gall I, Israeli D, Dausset J, Siguax F, Chumakov I, Oren M, Calvo F, Amson RB, Cohen D and Telerman A. . 1996 Proc. Natl. Acad. Sci. USA 93: 9039–9042.

  • Oltvai ZN, Milliman CL and Korsmeyer SJ. . 1993 Cell 74: 609–619.

  • Ostermeyer AG, Runko E, Winkfield B, Ahn B and Moll UM. . 1996 Proc. Natl. Acad. Sci. USA 93: 15190–15194.

  • Pirollo KF, Hao Z, Rait A, Jang YJ, Fee Jr WE, Ryan P, Chiang Y and Chang EH. . 1997 Oncogene 14: 1735–1746.

  • Polyak K, Xia Y, Zweier JL, Kinzler KW and Vogelstein B. . 1997 Nature 389: 300–305.

  • Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C and DePinho RA. . 1998 Cell 92: 713–723.

  • Roth J, Dobbelstein M, Freedman DA, Shenk T and Levine AJ. . 1998 EMBO J. 17: 554–564.

  • Roth JA, Nguyen D, Lawrence DD, Kemp BL, Carrasco CH, Ferson DZ, Hong WK, Komaki R, Lee JJ, Nesbitt JC, Pisters KM, Putnam JB, Schea R, Shin DM, Walsh GL, Dolormente MM, Han CI, Martin FD, Yen N, Xu K, Stephens LC, McDonnell TJ, Mukhopadhyay T and Cai D. . 1996 Nat. Med. 2: 985–991.

  • Roy C, Brown DL, Little JE, Valentine BK, Walker PR, Sikorska M, Leblanc J and Chaly N. . 1992 Exp. Cell. Res. 200: 416–424.

  • Sabbatini P, Chiou SK, Rao L and White E. . 1995 Mol. Cell. Biol. 15: 1060–1070.

  • Sakai E and Tsuchida N. . 1992 Oncogene 7: 927–933.

  • Sankaranarayanan R, Masuyer E, Swaminathan R, Ferlay J and Whelan S. . 1998 Anticancer Res. 18: 4779–4786.

  • Sarnow P, Ho YS, Williams J and Levine AJ. . 1982 Cell 28: 387–394.

  • Scheffner M, Munger K, Byrne JC and Howley PM. . 1991 Proc. Natl. Acad. Sci. USA 88: 5523–5527.

  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ and Howley PM. . 1990 Cell 63: 1129–1136.

  • Schuler M, Rochlitz C, Horowitz JA, Schlegel J, Perruchoud AP, Kommoss F, Bolliger CT, Kauczor HU, Dalquen P, Fritz MA, Swanson S, Hermann R and Huber C. . 1998 Hum. Gene Ther. 9: 2075–2082.

  • Selivanova G, Iotsova V, Okan I, Fritsche M, Strom M, Groner B, Grafstrom RC and Wiman KG. . 1997 Nat. Med. 3: 632–638.

  • Shah GM, Shah RG and Poirier GG. . 1996 Biochem. Biophys. Res. Commun. 229: 838–844.

  • Shah JP and Lydiatt W. . 1995 CA Cancer J. Clin. 45: 352–368.

  • Slack RS, Belliveau DJ, Rosenberg M, Atwal J, Lochmuller H, Aloyz R, Haghighi A, Lach B, Seth P, Cooper E and Miller FD. . 1996 J. Cell. Biol. 135: 1085–1096.

  • Smith DF and Toft DO. . 1993 Mol. Endocrinol. 7: 4–11.

  • Stommel JM, Marchenko ND, Jimenez GS, Moll UM, Hope TJ and Wahl GM. . 1999 EMBO J. 18: 1660–1672.

  • Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH and Peters G. . 1998 EMBO J. 17: 5001–5014.

  • Treinies I, Paterson HF, Hooper S, Wilson R and Marshall CJ. . 1999 Mol. Cell. Biol. 19: 321–329.

  • Vater CA, Bartle LM, Dionne CA, Littlewood TD and Goldmacher VS. . 1996 Oncogene 13: 739–748.

  • Vojtesek B, Bartek J, Midgley CA and Lane DP. . 1992 J. Immunol. Methods 151: 237–244.

  • Wakeling AE. . 1995 Biochem. Pharmacol. 49: 1545–1549.

  • Waldman T, Lengauer C, Kinzler KW and Vogelstein B. . 1996 Nature 381: 713–716.

  • Wasylyk C, Salvi R, Argentini M, Dureuil C, Delumeau I, Abecassis J, Debussche L and Wasylyk B. . 1999 Oncogene 18: 1921–1934.

  • Werness BA, Levine AJ and Howley PM. . 1990 Science 248: 76–79.

  • White J, Brou C, Wu J, Lutz Y, Moncollin V and Chambon P. . 1992 EMBO J. 11: 2229–2240.

  • Wieczorek AM, Waterman JL, Waterman MJ and Halazonetis TD. . 1996 Nat. Med. 2: 1143–1146.

  • Xu GW, Sun ZT, Forrester K, Wang XW, Coursen J and Harris CC. . 1996 Hepatology 24: 1264–1268.

  • Yew PR, Liu X and Berk AJ. . 1994 Genes Dev. 8: 190–202.

  • Yin C, Knudson CM, Korsmeyer SJ and Van Dyke T. . 1997 Nature 385: 637–640.

  • Yonish-Rouach E, Deguin V, Zaitchouk T, Breugnot C, Mishal Z, Jenkins JR and May E. . 1995 Oncogene 11: 2197–2205.

  • Zauberman A, Lupo A and Oren M. . 1995 Oncogene 10: 2361–2366.

Download references

Acknowledgements

We would like to acknowledge: (a) members of IFCPAR/CEFIPRA (Indo-French Centre for the Promotion of Advanced Research) for their scientific support, judgement and financial assistance, (b) members of Rhone-Poulenc Rorer (RPR), especially E Conseiller, L Debussche, L Bracco and B Tocque for providing recombinants and discussions, (c) J Shay, B Vogelstein, M Oren, J Reed and A Levine for gifts of recombinants, (d) L Andera and G de Murcia for the antibodies, (e) N Tsuchida for HSC-2 cell line, (f) A Wakeliing and Zeneca Pharmaceuticals for the anti-oestrogens, (g) H Zheng for the construction of ERT1-CTS and ERT2-CTS, (h) IGBMC core and cell culture facilities for help and support and (i) the members of Boh Wasylyk lab for constructive discussions. S Sengupta would like to acknowledge Geetha Vani Rayasam for her constant support and critical reading of the manuscript. A fellowship to S Sengupta from the IFCPAR is gratefully acknowledged. We would also like to thank for financial assistance: BioAvenir, the Centre National de la Recherche Scientifique, the Institute National de la Santé et de la Recherche Mèdicale, the Hospital Universitaire de Strasbourg, the Association pour la Recherche sur la Cancer, the Foundation pour la Recherche Médicale, the Ligue National Française contre le Cancer, the Ligue Regionale (Haut-Rhin) contre le Cancer and the Ligue Règionale (Bas-Rhin) contre le Cancer.

Author information

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, BP 163, Illkirch cedex, 67404, France

    Sagar Sengupta & Bohdan Wasylyk

  2. All India Institute for Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Ranju Ralhan

Authors
  1. Sagar Sengupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ranju Ralhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bohdan Wasylyk
    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

Sengupta, S., Ralhan, R. & Wasylyk, B. Tumour regression in a ligand inducible manner mediated by a chimeric tumour suppressor derived from p53. Oncogene 19, 337–350 (2000). https://doi.org/10.1038/sj.onc.1203256

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203256

Keywords

This article is cited by

Search

Advanced search

Quick links