Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways

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  • An Erratum to this article was published on 01 March 1998

Abstract

Atm is part of a pathway that responds to DMA damage from ionizing radiation (IR). This pathway involves p53 as Atm-deficient cell lines and mice are defective in p53 induction after IR15. p53 is a multi-functional protein that simultaneously regulates distinct downstream pathways controlling cell-cycle progression and apoptosis6,7. However, the mechanisms by which p53 differentially activates downstream pathways are unknown. To determine the relationship between Atm and p53, we examined cell-cycle and apoptotic responses in Atm-, p53- (ref. 8) and p27-deficient9 mice after IR in the whole animal. As expected, p53 protein levels were not induced by IR in thymus of Atm-deiicient mice. IR-induced cell-cycle checkpoint function was also defective, and induction of p21 was attenuated in thymus from >U/7?-deficient mice. However, IR-induced apoptosis and Bax induction were completely normal; both of which are mediated by p53. IR-induced thymic apoptosis was suppressed in Atm/p53 double-mutant mice but not in Atm/p21 double mutants, demonstrating p53 dependence and Atm independence. Thus, Atm deficiency results in lack of p53 induction by IR, but only selective disruption of p53-dependent functions. Our results support a model in which upstream effectors such as Atm selectively activate p53 to regulate specific downstream pathways, providing a mechanism for controlling distinct cell-cycle and apoptotic responses.

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References

  1. 1

    Kastan, M.B. et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71, 587–597 (1992).

  2. 2

    Lu, X. & Lane, D.P. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell 75, 765–778 (1993).

  3. 3

    Khanna, K.K. & Lavin, M.F. Ionizing radiation and UV induction of p53 protein by different pathways in ataxia-telangiectasia cells. Oncogene 8, 3307–3312 (1993).

  4. 4

    Xu, Y. & Baltimore, D. Dual responses of ATM in the cellular response to irradiation and in cell growth. Genes Dev. 10, 2401–2410 (1996).

  5. 5

    Baskaran, R. et al. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 387, 516–519 (1997).

  6. 6

    Ko, L.J. & Prives, C. p53: puzzle and paradigm. Genes Dev. 10, 1054–1072 (1996).

  7. 7

    Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

  8. 8

    Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994).

  9. 9

    Deng, C., Zhang, P., Harper, J.W., Elledge, S.J. & Leder, P. Mice lacking p21clp1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675–684 (1995).

  10. 10

    Shiloh, Y. Ataxia-telangiectasia: closer to unraveling the mystery. Eur. J. Hum. Genet. 3, 116–38 (1995).

  11. 11

    Meyn, M.S. Ataxia-telangiectasia and cellular responses to DNA damage. Cancer Res. 55, 5991–6001 (1995).

  12. 12

    Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).

  13. 13

    Meyn, M.S., Strasfeld, L. & Alien, C. Testing the role of p53 in the expression of genetic instability and apoptosis in ataxia-telangiectasia. Int. J. Radiat. Biol. 66, 5141–5149 (1994).

  14. 14

    Westphal, C.H. et al atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nature Genet. 16, 397–401 (1997).

  15. 15

    Kastan, M.B., Onyekwere, O., Sidransky, D., Vogelstein, B. & Craig, R.W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304–6311 (1991).

  16. 16

    Brugarolas, J. et al. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377, 552–557 (1995).

  17. 17

    Lowe, S.W., Schmitt, E.M., Smith, S.W., Osborne, B.A. & Jacks, T. p53 is required for radiation-indiced apaptosis in mouse thymocytes. Nature 362, 847–849 (1993).

  18. 18

    Clarke, A.R. et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362, 849–852 (1993).

  19. 19

    Santana, P. et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 86, 189–199 (1996).

  20. 20

    Chen, G. & Lee, E.Y.H.-P. The product of the ATM gene is a 370-kDa nuclear phosphoprotein. J.Biol. Chem. 271, 33693–33697 (1996).

  21. 21

    Lakin, N.D. et al. Analysis of the ATM protein in wild-type and ataxia telangiectasia cells. Oncogene 13, 2707–2716 (1996).

  22. 22

    Brown, K.D. et al. The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not upregulated following genome damage. Proc. Natl.Acad. Sci. USA 94, 1840–1845 (1997).

  23. 23

    EI-Deiry, W.S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 (1993).

  24. 24

    Harper, J.W., Adami, G.R., Wei, N., Keyomarsi, K. & Elledge, S.J. The p21 cdk-interacting protein Cip1 is a potent inhibitor of G1-cyclin-dependent kinases. Cell 75, 805–816 (1993).

  25. 25

    Miyashita, T. & Reed, J.C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293–299 (1995).

  26. 26

    Friedlander, P., Haupt, Y., Prives, C. & Oren, M. A mutant p53 that discriminates between p53-responsive genes and cannot induce apoptosis.Mol. Cell. Biol. 16, 4961–4971 (1996).

  27. 27

    Chen, X., Ko, L.J., Jayaraman, L. & Prives, C. p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. Genes Dev. 10, 2438–2451 (1996).

  28. 28

    Pietenpol, J.A. et al. Sequence-specific transcriptional activation is essential for growth suppression by p53. Proc. Natl.Acad. Sci. USA 91, 1998–2002 (1994).

  29. 29

    White, R.A., Terry, N.H., Meistrich, M.L. & Calkins, D.P. Improved method for computing potential doubling time from flow cytometric data. Cytometry 11, 314–317 (1990).

  30. 30

    Luna, L.G. Methods and Color Atlas of Special Stainss and Tissue (American Histolabs, Gaithersburg, Maryland, 1992).

  31. 31

    Harlow, E. & Lane, D. Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1988).

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Barlow, C., Brown, K., Deng, C. et al. Atm selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways. Nat Genet 17, 453–456 (1997) doi:10.1038/ng1297-453

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