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.

The radioprotective effect of the 24 kDa FGF-2 isoform in HeLa cells is related to an increased expression and activity of the DNA dependent protein kinase (DNA-PK) catalytic subunit

Abstract

We previously reported that overexpression of the 24 kDa basic fibroblast factor (or FGF-2) isoform provides protection from the cytotoxic effect of ionizing radiation (IR). DNA double-strand breaks (DSB), the IR-induced lethal lesions, are mainly repaired in human cells by non-homologous end joining system (NHEJ). NHEJ reaction is dependent on the DNA-PK holoenzyme (composed of a regulatory sub-unit, Ku, and a catalytic sub-unit, DNA-PKcs) that assembles at sites of DNA damage. We demonstrated here that the activity of DNA-PK was increased by twofold in two independent radioresistant cell lines, HeLa 3A and CAPAN A3, overexpressing the 24 kDa FGF-2. This increase was associated with an overexpression of the DNA-PKcs without modification of Ku expression or activity. This overexpression was due to an up-regulation of the DNA-PKcs gene transcription by the 24 kDa FGF-2 isoform. Finally, HeLa 3A cells exhibited the hallmarks of phenotypic changes associated with the overexpression of an active DNA-PKcs. Indeed, a faster repair rate of DSB and sensitization to IR by wortmannin was observed in these cells. Our results represent the characterization of a new mechanism of control of DNA repair and radioresistance in human tumor cells dependent on the overproduction of the 24 kDa FGF-2 isoform.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  • Anderson CW, Carter TH . 1996 Curr. Top. Microbiol. Immunol. 217: 91–111

  • Bikfalvi A, Klein S, Pintucci G, Quarto N, Mignatti P, Rifkin DB . 1995 J. Cell Biol. 129: 233–243

  • Bonnet H, Filhol O, Truchet I, Brethenou P, Cochet C, Amalric F, Bouche G . 1996 J. Biol. Chem. 271: 24781–24787

  • Boulton S, Kyle S, Yalcintepe L, Durkacz BW . 1996 Carcinogenesis 17: 2285–2290

  • Bugler B, Amalric F, Prats H . 1991 Mol. Cell. Biol. 11: 573–577

  • Cohen-Jonathan E, Toulas C, Monteil S, Couderc B, Maret A, Bard JJ, Prats H, Daly-Schveitzer N, Favre G . 1997 Cancer Res. 57: 1364–1370

  • Connelly MA, Zhang H, Kieleczawa J, Anderson CW . 1998 Genomics 47: 71–83

  • Estival A, Yken N, Escaffit F, Bertrand C, Pradayrol L, Clemente F . 2001 Int. J. Medecine 8: S88

  • Fertil B, Dertinger H, Courdi A, Malaise EP . 1984 Radiat. Res. 99: 73–84

  • Finnie NJ, Gottlieb TM, Blunt T, Jeggo PA, Jackson SP . 1995 Proc. Natl. Acad. Sci. USA 92: 320–324

  • Foray N, Priestley A, Alsbeih G, Badie C, Capulas EP, Arlett CF, Malaise EP . 1997 Int. J. Radiat. Biol. 72: 271–283

  • Frank KM, Sekiguchi JM, Seidl KJ, Swat R, Rathbun GA, Cheng HL, Davidson L, Kangaloo L, Alt FW . 1998 Nature 396: 173–177

  • Fujimoto M, Matsumoto N, Tsujita T, Tomita H, Kondo S, Miyake N, Nakano M, Niikawa N . 1997 DNA Res. 4: 151–154

  • Fuks Z, Persaud RS, Alfieri A, McLoughlin M, Ehleiter D, Schwartz JL, Seddon AP, Cordon-Cardo C, Haimovitz-Friedman A . 1994 Cancer Res. 54: 2582–2590

  • Gao Y, Chaudhuri J, Zhu C, Davidson L, Weaver DT, Alt FW . 1998a Immunity 9: 367–376

  • Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ, Sekiguchi JM, Rathbun GA, Swat W, Wang J, Bronson RT, Malynn BA, Bryans M, Zhu C, Chaudhuri J, Davidson L, Ferrini R, Stamato T, Orkin SH, Greenberg ME, Alt FW . 1998b Cell 95: 891–902

  • Godwin AR, Bollag RJ, Christie DM, Liskay RM . 1994 Proc. Natl. Acad. Sci. USA 91: 12554–12558

  • Gottlieb TM, Jackson SP . 1993 Cell 72: 131–142

  • Grein S, Pyerin W . 1999 Mol. Cell Biochem. 191: 121–128

  • Guo C, Davis AT, Yu S, Tawfic S, Ahmed K . 1999 Mol. Cell Biochem. 191: 135–142

  • Han Z, Johnston C, Reeves WH, Carter T, Wyche JH, Hendrickson EA . 1996 J. Biol. Chem. 271: 14098–14104

  • Hartley KO, Gell D, Smith GC, Zhang H, Divecha N, Connelly MA, Admon A, Lees-Miller SP, Anderson CW, Jackson SP . 1995 Cell 82: 849–856

  • Jeggo PA . 1998 Adv. Genet. 38: 185–218

  • Kurimasa A, Kumano S, Boubnov NV, Story MD, Tung CS, Peterson SR, Chen DJ . 1999 Mol. Cell Biol. 19: 3877–3884

  • Laborda J . 1991 Nucleic Acids Res. 19: 3998

  • Mimori T, Hardin JA . 1986 J. Biol. Chem. 261: 10375–10379

  • Muller C, Calsou P, Frit P, Cayrol C, Carter T, Salles B . 1998b Nucleic Acids Res. 26: 1382–1389

  • Muller C, Christodoulopoulos G, Salles B, Panasci L . 1998c Blood 92: 2213–2219

  • Muller C, Dusseau C, Calsou P, Salles B . 1998a Oncogene 16: 1553–1560

  • Okada T, Sakuma L, Fukui Y, Hazeki O, Ui M . 1994 J. Biol. Chem. 269: 3563–3567

  • Ouyang H, Nussenzweig A, Kurimasa A, Soares VC, Li X, Cordon-Cardo C, Li W, Cheong N, Nussenzweig M, Iliakis G, Chen DJ, Li GC . 1997 J. Exp. Med. 186: 921–929

  • Prats H, Kaghad M, Prats AC, Klagsbrun M, Lelias JM, Liauzun P, Chalon P, Tauber JP, Amalric F, Smith JA . 1989 Proc. Natl. Acad. Sci. USA 86: 1836–1840

  • Price BD, Youmell MB . 1996 Cancer Res. 56: 246–250

  • Renko M, Quarto N, Morimoto T, Rifkin DB . 1990 J. Cell Physiol. 144: 108–114

  • Santiago FS, Lowe HC, Bobryshev YV, Khachigian LM . 2001 J. Biol. Chem. 276: 41143–41149

  • Sargent RG, Brenneman MA, Wilson JH . 1997 Mol. Cell Biol. 17: 267–277

  • Sarkaria JN, Tibbetts RS, Busby EC, Kennedy AP, Hill DE, Abraham RT . 1998 Cancer Res. 58: 4375–4382

  • Shen B, Arese M, Gualandris A, Rifkin DB . 1998b Biochem. Biophys. Res. Commun. 252: 524–528

  • Shen H, Schultz M, Kruh GD, Tew KD . 1998a Biochim. Biophys. Acta 1381: 131–138

  • Smith GC, Jackson SP . 1999 Genes Dev. 13: 916–934

  • Spencer JA, Major ML, Misra RP . 1999 Mol. Cell Biol. 19: 3977–3988

  • Stachowiak EK, Maher PA, Tucholski J, Mordechai E, Joy A, Moffett J, Coons S, Stachowiak MK . 1997 Oncogene 14: 2201–2211

  • Takahashi JA, Mori H, Fukumoto M, Igarashi K, Jaye M, Oda Y, Kikuchi H, Hatanaka M . 1990 Proc. Natl. Acad. Sci. USA 87: 5710–5714

  • Van den BL, Laurell H, Huez I, Zanibellato C, Prats H, Bugler B . 2000 Mol. Endocrinol. 14: 1709–1724

  • Xu W, Liu L, Smith GC, Charles I . 2000 Nat. Cell Biol. 2: 339–345

  • Zagzag D, Miller DC, Sato Y, Rifkin DB, Burstein DE . 1990 Cancer Res. 50: 7393–7398

  • Zhang WW, Yaneva M . 1992 Biochem. Biophys. Res. Commun. 186: 574–579

  • Zhou Y, Gross W, Hong SH, Privalsky ML . 2001 Mol. Cell Biochem. 220: 1–13

  • Zhu C, Bogue MA, Lim DS, Hasty P, Roth DB . 1996 Cell 86: 379–389

Download references

Acknowledgements

We thank CW Anderson (Brookhaven National Laboratory, New York, USA) for DNA-PKcs reporter plasmid, T Lindhal (London, UK) for anti-ligase IV antibody. We also thank A Estival and F Clemente (INSERM U531, Toulouse, France) for providing CAPAN-1 and CAPAN A3 cells. This work was supported by the Ministere de la Recherche et de l'Enseignement Supérieur (I Ader, E Cohen-Jonathan, G Favre, C Muller and B Salles), by the Ligue Nationale Contre le Cancer, by Electricité de France (C Toulas) and by the Groupe de Recherche de l'Institut Claudius Regaud (C Toulas, E Cohen-Jonathan and G Favre).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christine Toulas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ader, I., Muller, C., Bonnet, J. et al. The radioprotective effect of the 24 kDa FGF-2 isoform in HeLa cells is related to an increased expression and activity of the DNA dependent protein kinase (DNA-PK) catalytic subunit. Oncogene 21, 6471–6479 (2002). https://doi.org/10.1038/sj.onc.1205838

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205838

Keywords

This article is cited by

Search

Quick links