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  • Original Paper
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ATM complexes with HDM2 and promotes its rapid phosphorylation in a p53-independent manner in normal and tumor human cells exposed to ionizing radiation

Oncogene volume 19, pages 6185–6193 (2000)Cite this article

Abstract

To further understand the mechanism(s) by which DNA damage activates p53, we analysed the expression levels of p53 and HDM2 (the human homolog of murine MDM2) in various human diploid fibroblast and tumor cell strains during the period that precedes activation of known downstream effectors of p53. In X-irradiated human cells, HDM2 protein was rapidly phosphorylated in serine/threonine residues in a p53, p14ARF and p73-independent manner. In p53 wild-type cells, HDM2 phosphorylation precedes a detectable increase in the levels of p53 and is not observed in ataxia telangiectasia (AT) fibroblasts. The transfection of AT cells with a vector expressing ATM restored the ability to rapidly phosphorylate HDM2 following X-irradiation, confirming a role for ATM in its phosphorylation. We also show that ATM complexes with HDM2. The DNA lesions signaling the early rapid phosphorylation of HDM2 are a result of X-ray and not UV-type damage. The ATM-promoted early covalent modification of HDM2 in X-irradiated human cells may provide a mechanism to activate p53.

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References

  • Abraham J, Spaner D and Benchimol S. . 1999 Oncogene 18: 1521–1527.

  • Ashcroft M and Vousden KH. . 1999 Oncogene 18: 7637–7643.

  • Ashcroft M, Kubbutat MH and Vousden KH. . 1999 Mol. Cell Biol. 19: 1751–1758.

  • Azzam EI, de Toledo SM, Pykett MJ, Nagasawa H and Little JB. . 1997 Cell Growth Differ. 8: 1161–1169.

  • Banin S, Moyal L, Shieh S-Y, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y and Ziv Y. . 1998 Science 281: 1674–1677.

  • Blattner C, Tobiasch E, Liften M, Rahmsdorf HJ and Herrlich P. . 1999 Oncogene 18: 1723–1732.

  • Boulikas T. . 1995 Crit. Rev. Eukaryot. Gene Expr. 5: 1–77.

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

  • Chehab NH, Malikzay A, Stavridi ES and Halazonetis TD. . 1999 Proc. Natl. Acad. Sci. USA 96: 13777–13782.

  • Chen L, Lu W, Agarwal S, Zhou W, Zhang R and Chen J. . 1999 Mol. Med. 5: 21–34.

  • Chomczynski P and Sacchi N. . 1987 Anal. Biochem. 162: 156–159.

  • de Toledo SM, Azzam EI, Gasmann MK and Mitchel REJ. . 1995 Int. J. Radiat. Biol. 67: 135–143.

  • de Toledo SM, Azzam EI, Keng P, Laffrenier S and Little JB. . 1998 Cell Growth Differ. 9: 887–896.

  • Finlay CA. . 1993 Mol. Cell. Biol. 13: 301–306.

  • Freedman DA, Wu L and Levine AJ. . 1999 Cell. Mol. Life Sci. 55: 96–107.

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

  • Grossman SR, Perez M, Kung AL, Joseph M, Mansur C, Xiao Z-X, Kumar S, Howley PM and Livingston DM. . 1998 Mol. Cell 2: 405–415.

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

  • Honda R, Tanaka H and Yasuda H. . 1997 FEBS Lett. 420: 25–27.

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

  • Khanna KK and Lavin MF. . 1993 Oncogene 8: 3307–3312.

  • Khosravi R, Maya R, Gottleib T, Oren M, Shiloh Y and Shkedy D. . 1999 Proc. Natl. Acad. Sci. USA 96: 14973–14977.

  • Kong Y-Y, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ and Mak TW. . 2000 Science 287: 1824–1827.

  • Kubuttat MHG, Jones SN and Vousden KH. . 1997 Nature 387: 299–303.

  • Kuerbitz SJ, Plunkett BS, Walsh WV and Kastan MB. . 1992 Proc. Natl. Acad. Sci. USA 89: 7491–7495.

  • Landers JE, Cassel SL and George DL. . 1997 Cancer Res. 57: 3562–3568.

  • Lavin MF and Khanna KK. . 1999 Int. J. Radiat. Biol. 75: 1201–1214.

  • Little JB and Nagasawa H. . 1985 Radiat. Res. 101: 81–93.

  • Liu Z-G, Baskaran R, Lea-Chou ET, Wood LD, Chen Y, Karin M and Wang VYJ. . 1996 Nature 384: 273–276.

  • Maki CG, Huibregtse JM and Howley PM. . 1996 Cancer Res. 56: 2649–2654.

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

  • Maltzman W and Czyzyk L. . 1984 Mol. Cell. Biol. 4: 1689–1694.

  • Meek DW. . 1999 Oncogene 18: 7666–7675.

  • Midgley CA, Lane DP. . 1997 Oncogene 15: 1179–1189.

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

  • Nelson WG and Kastan MB. . 1994 Mol. Cell. Biol. 14: 1815–1823.

  • Olson DC, Marechal V, Momand J, Chen J, Romocki C and Levine AJ. . 1993 Oncogene 8: 2353–2360.

  • Picksley SM, Vojtesek B, Sparks A and Lane DP. . 1994 Oncogene 9: 2523–2529.

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

  • Prives C. . 1998 Cell 95: 5–8.

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

  • Rotman G and Shiloh Y. . 1999 Oncogene 18: 6135–6144.

  • Sionov RV, Moallem E, Berger M, Kazaz A, Gerlitz O, Ben-Neriah Y, Oren M and Haupt Y. . 1999 J. Biol. Chem. 274: 8371–8374.

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

  • Tao W and Levine AJ. . 1999 Proc. Natl. Acad. Sci. USA 96: 6937–6941.

  • Unger T, Juven-Gershon T, Moallem E, Berger M, Sionov RV, Lozano G, Oren M and Haupt Y. . 1999 EMBO J. 18: 1805–1814.

  • Wu L and Levine AJ. . 1997 Mol. Med. 3: 441–451.

  • Zeng X, Chen L, Jost CA, Maya R, Keller D, Wang X, Kaelin Jr WG, Oren M, Chen J and Lu H. . 1999 Mol. Cell. Biol. 19: 3257–3266.

  • Ziv Y, Bar-Shira A, Pecker I, Russell P, Jorgensen TJ, Tsarfati I and Shiloh Y. . 1997 Oncogene 15: 159–167.

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Acknowledgements

We are grateful to Yosef Shiloh for providing the vectors used in the study. We thank Drs Zhi-Min Yuan, Carl Maki, Leslie Jardine and Jijie Gu for helpful discussions. SM de Toledo, EI Azzam and WK Dahlberg contributed equally to this study. This work was supported by NIH Research grant CA-47542 and Center Grant ES-00002.

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  1. Edouard I Azzam

    Present address: Department of Radiology, New Jersey Medical School, Newark, 07103, NJ, USA

Authors and Affiliations

  1. Department of Cancer Cell Biology, Harvard School of Public Health, Laboratory of Radiobiology, Boston, MA 02115, Massachusetts, USA

    Sonia M de Toledo, Edouard I Azzam, William K Dahlberg, Tamara B Gooding & John B Little

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  1. Sonia M de Toledo
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  2. Edouard I Azzam
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de Toledo, S., Azzam, E., Dahlberg, W. et al. ATM complexes with HDM2 and promotes its rapid phosphorylation in a p53-independent manner in normal and tumor human cells exposed to ionizing radiation. Oncogene 19, 6185–6193 (2000). https://doi.org/10.1038/sj.onc.1204020

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