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Restoration of transcriptional activity of p53 mutants in human tumour cells by intracellular expression of anti-p53 single chain Fv fragments

Oncogene volume 18, pages 551–557 (1999)Cite this article

Abstract

We report here the production and the properties of single chain Fv fragments (scFvs) derived from the anti-p53 monoclonal antibodies PAb421 and 11D3. 11D3 is a newly generated monoclonal antibody which exhibits properties very comparable to those of PAb421. The scFvs PAb421 and 11D3 are able to stably associate with p53 and to restore the DNA binding activity of some p53 mutants in vitro. When expressed in p53−/− human tumour cells, the scFv421 is essentially localized in the cytoplasm in the absence of p53, and in the nucleus when exogenous p53 is present. Thus, p53 is also able to stably associate with an anti-p53 scFv in cells. Cotransfection of p53−/− human tumour cells with expression vectors encoding the His273 p53 mutant and either scFv leads to restoration of the p53 mutant deficient transcriptional activity. These data demonstrate that, in human tumour cells, these scFvs are able to restore a function essential for the tumour suppressor activity of p53 and may represent a novel class of molecules for p53-based cancer therapy.

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References

  • Abarzua P, LoSardo JE, Gubler ML and Neri A. . 1995 Cancer Res. 55: 3490–3494.

  • Abarzua P, LoSardo JE, Gubler ML, Spathis R, Lu YA, Felix A and Neri A. . 1996 Oncogene 13: 2477–2482.

  • Baker SJ, Markowitz S, Fearon ER, Willson JK and Vogelstein B. . 1990 Science 249: 912–915.

  • Bayle JH, Elenbaas B and Levine AJ. . 1995 Proc. Natl. Acad. Sci. USA 92: 5729–5733.

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

  • Byk G, Scherman D and Schwartz B. . Patent submitted in France 95 01865 (17/2/1995) WO 9625508-A1.

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

  • Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML and Wyllie AH. . 1993 Nature 362: 849–852.

  • Cochet O, Kenigsberg M, Delumeau I, Virone-Oddos A, Multon M-C, Fridman WH, Schweighoffer F, Teillaud J-L and Tocqué B. . 1998 Cancer Res. 58: 1170–1176.

  • Eizenberg O, Faber-Elman A, Gottlieb E, Oren M, Rotter V and Schwartz M. . 1995 EMBO J. 14: 1136–1144.

  • 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.

  • Finlay CA, Hinds PW and Levine AJ. . 1989 Cell 57: 1083–1093.

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

  • Guillouf C, Rosselli F, Krishnaraju K, Moustacchi E, Hoffman B and Liebermann DA. . 1995 Oncogene 10: 2263–2270.

  • Hainaut P, Soussi T, Shomer B, Hollstein M, Greenblatt M, Hovig E, Harris CC and Montesano R. . 1997 Nucl. Acids Res. 25: 151–157.

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

  • Halazonetis TD and Kandil AN. . 1993 EMBO J. 12: 5057–5064.

  • Harlow E, Crawford LV, Pim DC and Williamson NM. . 1981 J. Virol. 39: 861–869.

  • Hupp TR, Meek DW, Midgley CA and Lane DP. . 1992 Cell 71: 875–886.

  • Hupp TR, Meek DW, Midgley CA and Lane DP. . 1993 Nucl. Acids Res. 21: 3167–3174.

  • Hupp TR and Lane DP. . 1994 Curr. Biol. 4: 865–875.

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

  • Jannot CB and Hynes NE. . 1997 Biochem. Biophys. Res. Commun. 13: 242–246.

  • Kabat EA, Wu TT, Perry HM, Gottesman KS and Foeller C. . 1991 Sequences of proteins of immunological interest, 5th edition. US Department of Health and Human Services, Public Health Service, National Institute of Health, Bethesda, MD.

  • Kastan MB, Onyekwere O, Sidransky D, Vogelstein B and Craig RW. . 1991 Cancer Res. 51: 6304–6311.

  • Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B and Fornace Jr AJ. . 1992 Cell 71: 587–597.

  • Ko LJ and Prives C. . 1996 Genes Dev. 10: 1054–1072.

  • Lee S, Elenbaas B, Levine A and Griffith J. . 1995 Cell 81: 1013–1020.

  • Legros Y, Lafon C and Soussi T. . 1994 Oncogene 9: 2071–2076.

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

  • Lin J, Chen J, Elenbaas B and Levine AJ. . 1994 Genes Dev. 8: 1235–1246.

  • Lowe SW, Schmitt EM, Smith SW, Osborne BA and Jacks T. . 1993 Nature 362: 847–849.

  • Lu X and Lane DP. . 1993 Cell 75: 765–778.

  • Marasco WA. . 1997 Gene Ther. 4: 11–15.

  • Mercer WE, Shields MT, Amin M, Sauve GJ, Appella E, Romano JW and Ullrich SJ. . 1990 Proc. Natl. Acad. Sci. USA 87: 6166–6170.

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

  • Nieba L, Honegger A, Krebber C and Plucktun A. . 1997 Protein Eng. 10: 435–444.

  • Niewolik D, Vojtesek B and Kovarik J. . 1995 Oncogene 10: 881–890.

  • Orlandi R, Gussow DH, Jones PT and Winter G. . 1989 Proc. Natl. Acad. Sci. USA 86: 3833–3837.

  • 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.

  • Park DJ, Nakamura H, Chumakov AM, Said JW, Miller CW, Chen DL and Koeffler HP. . 1994 Oncogene 9: 1899–1906.

  • Pavletich NP, Chambers KA and Pabo CO. . 1993 Genes and Dev. 7: 2556–2564.

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

  • Richardson JH, Sodroski JG, Waldmann TA and Marasco WA. . 1995 Proc. Natl. Acad. Sci. USA 92: 3137–3141.

  • Smith ML, Chen IT, Zhan Q, O'Connor PM and Fornace Jr AJ. . 1995 Oncogene 10: 1053–1059.

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

  • Walker KK and Levine AJ. . 1996 Proc. Natl. Acad. Sci. USA 93: 15335–15340.

  • Waterman JL, Shenk JL and Halazonetis TD. . 1995 EMBO J. 14: 512–519.

  • Zhan Q, Carrier F and Fornace Jr AJ. . 1993 Mol. Cell. Biol. 13: 4242–4250.

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Acknowledgements

We thank Véronique Sierra for technical assistance and Dr Alain Aurias (Institut Curie, Paris, France) for getting access to fluorescence imaging system. This work was supported by the Institut Curie and by the French BIO AVENIR programme (MENESR).

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Authors and Affiliations

  1. Gene Medicine Department, Rhóne-Poulenc Rorer SA, 13 quai Jules Guesde, BP14, Vitry sur Seine, 94403, Cedex, France

    Claude Caron de Fromentel, Corinne Venot, Laurent Debussche, Emmanuel Conseiller, Christine Dureuil, Bruno Tocque & Laurent Bracco

  2. Laboratoire de Biotechnologie des Anticorps, France

    Nadége Gruel & Jean-Luc Teillaud

  3. Unité INSERM 255, Institut Curie, 26, rue d'Ulm, Paris, 75005, France

    Jean-Luc Teillaud

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  1. Claude Caron de Fromentel
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Caron de Fromentel, C., Gruel, N., Venot, C. et al. Restoration of transcriptional activity of p53 mutants in human tumour cells by intracellular expression of anti-p53 single chain Fv fragments. Oncogene 18, 551–557 (1999). https://doi.org/10.1038/sj.onc.1202338

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