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The ups and downs of p53: understanding protein dynamics in single cells

Abstract

Cells living in a complex environment must constantly detect, process and appropriately respond to changing signals. Therefore, all cellular information processing is dynamic in nature. As a consequence, understanding the process of signal transduction often requires detailed quantitative analysis of dynamic behaviours. Here, we focus on the oscillatory dynamics of the tumour suppressor protein p53 as a model for studying protein dynamics in single cells to better understand its regulation and function.

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Figure 1: Dynamics in signal transduction pathways.
Figure 2: The p53 signalling network.
Figure 3: The response of p53 to DNA double strand breaks (DSBs).
Figure 4: Phase plane trajectories of oscillators and pulse generators.
Figure 5: Model for the potential role of ataxia telangiectasia mutated (ATM) pulses in the DNA repair process.
Figure 6: Pulsing transcription factors can give rise to multiple dynamic patterns of their target genes.

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References

  1. Cohen, A. A. et al. Dynamic proteomics of individual cancer cells in response to a drug. Science 322, 1511–1516 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Hoffmann, A., Levchenko, A., Scott, M. L. & Baltimore, D. The IκB–NF-κB signaling module: temporal control and selective gene activation. Science 298, 1241–1245 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Nelson, D. E. et al. Oscillations in NF-κB signaling control the dynamics of gene expression. Science 306, 704–708 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Nelson, D. E., See, V., Nelson, G. & White, M. R. Oscillations in transcription factor dynamics: a new way to control gene expression. Biochem. Soc. Trans. 32, 1090–1092 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Hilioti, Z. et al. Oscillatory phosphorylation of yeast Fus3 MAP kinase controls periodic gene expression and morphogenesis. Curr. Biol. 18, 1700–1706 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lane, D. P. Cancer. p53, guardian of the genome. Nature 358, 15–16 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Horn, H. F. & Vousden, K. H. Coping with stress: multiple ways to activate p53. Oncogene 26, 1306–1316 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Riley, T., Sontag, E., Chen, P. & Levine, A. Transcriptional control of human p53-regulated genes. Nature Rev. Mol. Cell Biol. 9, 402–412 (2008).

    Article  CAS  Google Scholar 

  11. Lev Bar-Or, R. et al. Generation of oscillations by the p53–Mdm2 feedback loop: a theoretical and experimental study. Proc. Natl Acad. Sci. USA 97, 11250–11255 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lahav, G. et al. Dynamics of the p53–Mdm2 feedback loop in individual cells. Nature Genet. 36, 147–150 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Geva-Zatorsky, N. et al. Oscillations and variability in the p53 system. Mol. Syst. Biol. 2, 2006 0033 (2006).

    Article  PubMed  Google Scholar 

  14. Batchelor, E., Mock, C. S., Bhan, I., Loewer, A. & Lahav, G. Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage. Mol. Cell 30, 277–289 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hamstra, D. A. et al. Real-time evaluation of p53 oscillatory behavior in vivo using bioluminescent imaging. Cancer Res. 66, 7482–7489 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Murray, J. D. Mathematical Biology (eds Antman, S. S., Marsden, J. E., Sirovich, L. & Wiggins, S.) 175–256 (Springer, New York, 2002).

    Google Scholar 

  17. Edelstein-Keshet, L. Mathematical Models in Biology 311–380 (Society for Industrial and Applied Mathematics, Philadelphia, 2005).

    Book  Google Scholar 

  18. Strogatz, S. H. Nonlinear Dynamics and Chaos 196–297 (Perseus Books Publishing, LLC, Cambridge, 1994).

    Google Scholar 

  19. Halloy, J., Lauzeral, J. & Goldbeter, A. Modeling oscillations and waves of cAMP in Dictyostelium discoideum cells. Biophys. Chem. 72, 9–19 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Tyson, J. J. & Murray, J. D. Cyclic AMP waves during aggregation of Dictyostelium amoebae. Development 106, 421–426 (1989).

    CAS  PubMed  Google Scholar 

  21. Leloup, J. C., Gonze, D. & Goldbeter, A. Limit cycle models for circadian rhythms based on transcriptional regulation in Drosophila and Neurospora. J. Biol. Rhythms 14, 433–448 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Nakajima, M. et al. Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro. Science 308, 414–415 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Johnson, C. H., Mori, T. & Xu, Y. A cyanobacterial circadian clockwork. Curr. Biol. 18, R816–R825 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pomerening, J. R., Sontag, E. D. & Ferrell, J. E. Jr. Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2. Nature Cell Biol. 5, 346–351 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Tyson, J. J., Csikasz-Nagy, A. & Novak, B. The dynamics of cell cycle regulation. Bioessays 24, 1095–1109 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Novak, B. & Tyson, J. J. Design principles of biochemical oscillators. Nature Rev. Mol. Cell Biol. 9, 981–991 (2008).

    Article  CAS  Google Scholar 

  27. Shreeram, S. et al. Wip1 phosphatase modulates ATM-dependent signaling pathways. Mol. Cell 23, 757–764 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Fujimoto, H. et al. Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase. Cell Death Differ. 13 1170–1180 (2006).

  29. Lu, X., Nguyen, T. A. & Donehower, L. A. Reversal of the ATM/ATR-mediated DNA damage response by the oncogenic phosphatase PPM1D. Cell Cycle 4, 1060–1064 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Lu, X., Nannenga, B. & Donehower, L. A. PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev. 19, 1162–1174 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Proctor, C. J. & Gray, D. A. Explaining oscillations and variability in the p53–MDM2 system. BMC Syst. Biol. 2, 75 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Harris, S. L. & Levine, A. J. The p53 pathway: positive and negative feedback loops. Oncogene 24, 2899–2908 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Hodgkin, A. L. & Huxley, A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, 500–544 (1952).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fitzhugh, R. Impulses and physiological states in theoretical models of nerve membrane. Biophys. J. 1, 445–466 (1961).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fitzhugh, R. Thresholds and plateaus in the Hodgkin–Huxley nerve equations. J. Gen. Physiol. 43, 867–896 (1960).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nagumo, J., Arimoto, S. & Yoshizawa, S. An active pulse transmission line simulating nerve axon. Proc. IRE. 50, 2061–2070 (1962).

    Article  Google Scholar 

  37. Suel, G. M., Garcia-Ojalvo, J., Liberman, L. M. & Elowitz, M. B. An excitable gene regulatory circuit induces transient cellular differentiation. Nature 440, 545–550 (2006).

    Article  PubMed  Google Scholar 

  38. Murray, A. W. & Kirschner, M. W. Dominoes and clocks: the union of two views of the cell cycle. Science 246, 614–621 (1989).

    Article  CAS  PubMed  Google Scholar 

  39. Gonze, D. & Goldbeter, A. A model for a network of phosphorylation–dephosphorylation cycles displaying the dynamics of dominoes and clocks. J. Theor. Biol. 210, 167–186 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Mirzoeva, O. K. & Petrini, J. H. DNA damage-dependent nuclear dynamics of the Mre11 complex. Mol. Cell. Biol. 21, 281–288 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Berkovich, E., Monnat, R. J. Jr & Kastan, M. B. Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nature Cell Biol. 9, 683–690 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Lee, J. H. & Paull, T. T. ATM activation by DNA double-strand breaks through the Mre11–Rad50–Nbs1 complex. Science 308, 551–554 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Bekker-Jensen, S., Lukas, C., Melander, F., Bartek, J. & Lukas, J. Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1. J. Cell Biol. 170, 201–211 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Matsuoka, S. et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160–1166 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Cai, L., Dalal, C. K. & Elowitz, M. B. Frequency-modulated nuclear localization bursts coordinate gene regulation. Nature 455, 485–490 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wei, C. L. et al. A global map of p53 transcription-factor binding sites in the human genome. Cell 124, 207–219 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Lahav, G. The strength of indecisiveness: oscillatory behavior for better cell fate determination. Sci. STKE 2004, pe55 (2004).

    PubMed  Google Scholar 

  48. Zhang, T., Brazhnik, P. & Tyson, J. J. Exploring mechanisms of the DNA-damage response: p53 pulses and their possible relevance to apoptosis. Cell Cycle 6, 85–94 (2007).

    Article  PubMed  Google Scholar 

  49. Kruse, J. P. & Gu, W. SnapShot: p53 posttranslational modifications. Cell 133, 930–930.e1 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Brooks, C. L. & Gu, W. Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr. Opin. Cell Biol. 15, 164–171 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Bode, A. M. & Dong, Z. Post-translational modification of p53 in tumorigenesis. Nature Rev. Cancer 4, 793–805 (2004).

    Article  CAS  Google Scholar 

  52. Banin, S. et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281, 1674–1677 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Canman, C. E. et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281, 1677–1679 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Toledo, F. & Wahl, G. M. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nature Rev. Cancer 6, 909–923 (2006).

    Article  CAS  Google Scholar 

  55. Li, A. G. et al. An acetylation switch in p53 mediates holo-TFIID recruitment. Mol. Cell 28, 408–421 (2007).

    Article  PubMed  Google Scholar 

  56. Sims, R. J. 3rd & Reinberg, D. Is there a code embedded in proteins that is based on post-translational modifications? Nature Rev. Mol. Cell Biol. 9, 815–820 (2008).

    Article  CAS  Google Scholar 

  57. Murray-Zmijewski, F., Slee, E. A. & Lu, X. A complex barcode underlies the heterogeneous response of p53 to stress. Nature Rev. Mol. Cell Biol. 9, 702–712 (2008).

    Article  CAS  Google Scholar 

  58. Bond, G. L. et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119, 591–602 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Hu, W. et al. A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells. Cancer Res. 67, 2757–2765 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Bond, G. L. et al. MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res. 66, 5104–5110 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Petenkaya, A. et al. Lack of association between the MDM2-SNP309 polymorphism and breast cancer risk. Anticancer Res. 26, 4975–4977 (2006).

    CAS  PubMed  Google Scholar 

  62. Campbell, I. G., Eccles, D. M. & Choong, D. Y. No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer. Cancer Lett. 240, 195–197 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Krekac, D. et al. MDM2SNP309 does not associate with elevated MDM2 protein expression or breast cancer risk. Oncology 74, 84–87 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Ahn, J. Y., Schwarz, J. K., Piwnica-Worms, H. & Canman, C. E. Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation. Cancer Res. 60, 5934–5936 (2000).

    CAS  PubMed  Google Scholar 

  66. Matsuoka, S. et al. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc. Natl Acad. Sci. USA 97, 10389–10394 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chehab, N. H., Malikzay, A., Stavridi, E. S. & Halazonetis, T. D. Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc. Natl Acad. Sci. USA 96, 13777–13782 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Khosravi, R. et al. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc. Natl Acad. Sci. USA 96, 14973–14977 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wu, X., Bayle, J. H., Olson, D. & Levine, A. J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 7, 1126–1132 (1993).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all the members of our laboratory for useful discussions. This work was supported by National Institutes of Health Grant GM083303. E.B. was supported by the American Cancer Society, California Division, Pamela and Edward Taft Postdoctoral Fellowship.

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Batchelor, E., Loewer, A. & Lahav, G. The ups and downs of p53: understanding protein dynamics in single cells. Nat Rev Cancer 9, 371–377 (2009). https://doi.org/10.1038/nrc2604

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