Abstract
The ATM protein kinase is a critical intermediate in a number of cellular responses to ionizing irradiation (IR) and possibly other stresses. ATM dysfunction results in abnormal checkpoint responses in multiple phases of the cell cycle, including G1, S and G2. Though downstream targets of the ATM kinase are still being elucidated, it has been demonstrated that ATM acts upstream of p53 in a signal transduction pathway initiated by IR and can phosphorylate p53 at serine 15. The cell cycle stage-specificity of ATM activation and p53Ser15 phosphorylation was investigated in normal lymphoblastoid cell line (GM536). Ionizing radiation was found to enhance the kinase activity of ATM in all phases of the cell cycle. This enhanced activity was apparent immediately after treatment of cells with IR, but was not accompanied by a change in the abundance of the ATM protein. Since IR activates the ATM kinase in all phases of the cell cycle, DNA replication-dependent strand breaks are not required for this activation. Further, since p53 protein is not directly required for IR-induced S and G2-phase checkpoints, the ATM kinase likely has different functional targets in different phases of the cell cycle. These observations indicate that the ATM kinase is necessary primarily for the immediate response to DNA damage incurred in all phases of the cell cycle.
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Abbreviations
- IR:
-
ionizing radiation
- ATM:
-
ataxia telangiectasia mutant
References
Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y and Ziv Y . 1998 Science 281: 1674–1677
Bridges BA and Harnden DG . 1982 Ataxia Telangiectasia A Cellular and Molecular Link between Cancer, Neuropathology, and Immune Deficiency Wiley, Chichester, England
Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB and Siliciano JD . 1998 Science 281: 1677–1679
Canman CE, Wolff AC, Chen CY, Fornace Jr AJ and Kastan MB . 1994 Cancer Res 54: 5054–5058
Harnden DG . 1994 Int J Radiat Biol 66: S13–S19
Hartwell LH and Kastan MB . 1994 Science 266: 1821–1828
Hawley RS and Friend SH . 1996 Genes Dev 10: 2383–2388
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
Keith CT and Schreiber SL . 1995 Science 270: 50–51
Khanna KK and Lavin MF . 1993 Oncogene 8: 3307–3312
Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K, Taya Y, Gabrielli B, Chan D, Lees-Miller SP and Lavin MF . 1998 Nat Genet 20: 398–400
Maki CG, Huibregtse JM and Howley PM . 1996 Cancer Res 56: 2649–2654
Morgan SE and Kastan MB . 1997a Adv Can Res 71: 1–25
Morgan SE and Kastan MB . 1997b Cancer Res 57: 3386–3389
Morgan SE, Lovly C, Pandita TK, Shiloh Y and Kastan MB . 1997 Mol Cell Biol 17: 2020–2029
Morrow DM, Tagle DA, Shiloh Y, Collins FS and Hieter P . 1995 Cell 82: 831–940
Pandita TK and Hittelman WN . 1992a Rad Res 130: 94–103
Pandita TK and Hittelman WN . 1992b Rad Res 131: 214–223
Pandita TK, Westphal CH, Anger M, Sawant SG, Geard CR, Pandita RK and Scherthan H . 1999 Mol Cell Biol 19: 5096–5105
Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle D, Smith S, Uziel T, Sfez S, Ashkenazi A, Pecker I, Frydman M, Harnik R, Patanjali R, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanyal O, Lavin MF, Jaspers NGJ, Taylor AMR, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS and Shiloh Y . 1995a Science 268: 1749–1753
Savitsky K, Sfez S, Tagel DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y and Rotman G . 1995b Hum Mol Genet 4: 2025–2032
Shiloh Y . 1995 Eur J Hum Genet 3: 116–138
Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E and Kastan MB . 1997 Genes Dev 11: 3471–3481
Smilenov LB, Dhar S and Pandita TK . 1999 Mol Cell Biol 19: 6963–6971
Xu Y and Baltimore D . 1996 Genes Dev 10: 2401–2410
Acknowledgements
This work was supported by grants from NIH (NS34746, GM52493, CA71387, CA75061, ES05777), DOE (DE-FG07-96ER62309), and Columbia Cancer Center Breast Cancer Research Program. MB Kastan was the Steven Birbaum Scholar of the Leukemia Society of America and is supported by the American Lebanese Syrian Associated Charities (ALSAC) of St. Judes Children’s Research Hospital. HB Lieberman was supported by a NIH Research Career Development Award CA68446. Thanks are due to Lubomir B Smilenov, AS Balajee and Satin Sawant for their technical help.
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Pandita, T., Lieberman, H., Lim, DS. et al. Ionizing radiation activates the ATM kinase throughout the cell cycle. Oncogene 19, 1386–1391 (2000). https://doi.org/10.1038/sj.onc.1203444
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DOI: https://doi.org/10.1038/sj.onc.1203444
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