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Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin

Abstract

The CDK inhibitor p21waf is a principal mediator of p53 function but can also be transactivated by many p53-independent stimuli leading to cell growth arrest or differentiation. In order to study the function of p21waf in a p53-deficient environment, we established an inducible expression of p21waf in the p53-null lung cancer cell line H1299, based on the muristerone-regulated system. Overexpression of p21waf led cells to growth arrest which after several days became irreversible and the arrested cells acquired a senescent phenotype as judged by cell shape, the senescence-associated β-gal marker and inhibition of colony formation. The effect of p21waf overexpression, in the absence of p53, on the cytotoxicity caused by irradiation, doxorubicin and taxol was studied. Expression of p21waf provided protection against the cytotoxic effect of radiation and doxorubicin but not of taxol. These results are relevant to treatment of cancer when p53 is inactive.

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References

  • Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D and Barrett C. . 1996 Proc. Natl. Acad. Sci. USA 93: 13742–13747.

  • Bates S and Vousden KH. . 1996 Curr. Opin. Genet. Dev. 6: 12–18.

  • Brown JP, Wei W and Sedivy LM. . 1997 Science 277: 831–834.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Chedid M, Michieli P, Lengel C, Huppi K and Givol D. . 1994 Oncogene 9: 3021–3024.

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

    Article  CAS  Google Scholar 

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M and Campisi J. . 1995 Proc. Natl. Acad. Sci. USA 92: 9363–9367.

  • 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: 805–816.

  • Fazeli A, Steen RG, Dickinson SL, Bautista D, Dietrich WF, Bronson RT, Bresalier RS, Lander ES, Costa J and Weinberg RA. . 1997 Proc. Natl. Acad. Sci. USA 94: 10199–10204.

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D and Lassar A. . 1995 Science 267: 1018–1021.

    Article  CAS  Google Scholar 

  • Hansen R and Oren M. . 1997 Curr. Opin. Genet. Dev. 7: 46–51.

  • Harper JW and Elledge SJ. . 1996 Curr. Opin. Genet. Dev. 6: 56–64.

  • Harper JW, Adami GR, Wei N, Keyomarsi K and Elledge SJ. . 1993 Cell 75: 817–825.

    Article  CAS  Google Scholar 

  • Kondo Y, Kondom S, Liu J, Haqqi T, Barnett GH and Barna BP. . 1997 Exp. Cell. Res. 236: 51–56.

  • Maki CG and Howley PM. . 1997 Mol. Cell. Biol. 17: 355–363.

    Article  CAS  Google Scholar 

  • Michieli P, Chedid M, Lin D, Pierce JH, Mercer WE and Givol D. . 1994 Cancer Res. 54: 3391–3395.

  • No D, Yao TP and Evans RM. . 1997 Proc. Natl. Acad. Sci. USA 93: 3346–3351.

  • Noda A, Ning Y, Venable SF, Pereira-Smith OM and Smith JR. . 1994 Exp. Cell. Res. 211: 90–98.

  • Poluha W, Poluha DK, Chang B, Crosbie NE and Schonhoff CM. . 1996 Mol. Cell. Biol. 16: 1335–1341.

    Article  CAS  Google Scholar 

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

  • Sambrook J, Fritsch EF and Maniatis T. . 1989 Molecular Cloning: a Laboratory Manual Cold Spring Harbor Lab. Press, Plainview, NY 2nd Ed.

    Google Scholar 

  • Steinman RA, Hoffman B, Iro A, Guillouf C, Liebermann DA and El-Houseini ME. . 1994 Oncogene 9: 3389–3396.

  • Sugrue MM, Shin DY, Lee SW and Aaronson SA. . 1997 Proc. Natl. Acad. Sci. USA 94: 9648–9653.

  • Takahashi T, Carbone D, Takahashi T, Nau MM, Hida T, Linnoila I, Ueda R and Minna JD. . 1992 Cancer Res. 52: 2340–2343.

  • Uhrbom L, Nister M and Westermark B. . 1997 Oncogene 15: 505–514.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Waldman T, Zhang Y, Dillehay L, Yu J, Kinzler K, Vogelstein B and Williams J. . 1997 Nature Med. 3: 1034–1036.

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

  • Wang Y, Blandino G, Oren M and Givol D. . 1998 Oncogene 17: 1923–1930.

    Article  CAS  Google Scholar 

  • Wouters BG, Giaccia AJ, Denko NC and Brown JM. . 1997 Cancer Res. 57: 4703–4706.

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

    Article  CAS  Google Scholar 

  • Zakut R and Givol D. . 1995 Oncogene 11: 393–395.

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Acknowledgements

We thank Dr M Oren for cell line H1299Val135#3 and for helpful discussion, and Dr B Geiger for help in microscopy. GB acknowledges a fellowship from the Italian Association for Cancer Research (AIRC).

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Wang, Y., Blandino, G. & Givol, D. Induced p21waf expression in H1299 cell line promotes cell senescence and protects against cytotoxic effect of radiation and doxorubicin. Oncogene 18, 2643–2649 (1999). https://doi.org/10.1038/sj.onc.1202632

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