Abstract
The p53 tumour suppressor plays key regulatory roles in various fundamental biological processes, including development, ageing and cell differentiation. It is therefore known as “the guardian of the genome” and is currently the most extensively studied protein worldwide. Besides members of the biomedical community, who view p53 as a promising target for novel anti-cancer therapies, the complex network of protein interactions modulating p53’s activity has captivated the attention of theoreticians and modellers due to the possible occurrence of oscillations in protein levels in response to stress. This paper presents new insights into the behaviour of the p53 network, which we acquired by combining mathematical and experimental techniques. Notably, our data raises the question of whether the discrete p53 pulses in single cells, observed using fluorescent labelling, could in fact be an artefact. Furthermore, we propose a new model for the p53 pathway that is amenable to analysis by computational methods developed within the OPAALS project.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Abou-Jaude, W., Ouattara, D.A., Kaufman, M.: From structure to dynamics: Frequency tuning in the p53-mdm2 network. i. Logical approach. J. Theor. Biol. 258, 561–577 (2009)
Agrawal, S., Archer, C., Schaffer, D.V.: Computational models of the notch network elucidate mechanisms of context-dependent signaling, PLoS. Comput. Biol. 5, e1000390 (2009)
Ankers, J.M., Spiller, D.G., White, M.R.H., Harper, C.V.: Spatio-temporal protein dynamics in single living cells. Curr. Opinion Biotechnol. 19, 375–380 (2009)
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)
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)
Bernard, S., Cajavec, B., Pujo-Menjouet, L., Mackey, M.C., Herzel, H.: Modelling transcriptional feedback loops: the role of Gro/Tle1 in Hes1 oscillations. Phil. Trans. R. Soc. A 364, 1155–1170 (2006)
Bessho, Y., Kageyama, R.: Oscillations, clocks and segmentation. Curr. Opinion Gen. Dev. 13, 379–384 (2003)
Bier, M., Teusink, B., Kholodenko, B.N., Westerhoff, H.: Control analysis of gly-colytic oscillations. Biophys. Chem. 62, 15–24 (1996)
Bottani, S., Grammaticos, B.: Analysis of a minimal model for p53 oscillations. J. Theor. Biol. 249, 235–245 (2007)
Briscoe, G., Dini, P.: Towards Autopoietic Computing. In: Proceedings of the 3rd OPAALS International Conference, Aracaju, Sergipe, Brazil, March 22-23 (2010)
Byrne, H.M., van Leeuwen, I.M.M., Owen, M.R., Alarcon, T.A., Maini, P.K.: Multiscale modelling of solid tumour growth. In: Bellomo, N., Chaplain, M.A.J., de Angelis, E. (eds.) Selected Topics on Cancer Modelling: Genesis, Evolution, Immune Competition and Therapy. Modelling and Simulation in Science, Engineering and Technology, Birkhauser, Boston (2008)
Chickarmane, V., Nadim, A., Ray, A., Sauro, H.: A p53 oscillator model of dna break repair control (2006), http://arxiv.org/abs/q-bio.mn/0510002
Ciliberto, A., Novak, B., Tyson, J.J.: Steady states and oscillations in the p53/mdm2 network. Cell Cycle 4, 488–493 (2005)
Dequeant, M.L., Glynn, E., Gaudenz, K., Wahl, M., Chen, J., Mushegian, A., Pourquie, O.: A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science 314, 1595–1598 (2006)
Dini, P., Schreckling, D.: A Research Framework for Interaction Computing. In: Proceedings of the 3rd OPAALS International Conference, Aracaju, Sergipe, Brazil, March 22-23 (2010)
Dionysiou, D.D., Stamatakos, G.S.: Applying a 4D multiscale in vivo tumour growth model to the exploration of radiotherapy scheduling: the effects of weekend treatment gaps and p53 gene status on the response of fast growing solid tumors. Cancer Informatics 2, 113–121 (2006)
Egri-Nagy, A., Dini, P., Nehaniv, C.L., Schilstra, M.J.: Transformation Semigroups as Constructive Dynamical Spaces. In: Proceedings of the 3rd OPAALS International Conference, Aracaju, Sergipe, Brazil, March 22-23 (2010)
Farmer, G., Bargonetti, J., Zhu, H., Friedman, P., Prywes, R., Prives, C.: Wild-type p53 activates transcription in vivo. Nature 358, 83–84 (1992)
Geva-Zatorsky, N., Rosenfeld, N., Itzkovitz, S., Milo, R., Sigal, A., Dekel, E., Yarnitzky, T., Liron, Y., Polak, P., Lahav, G., Alon, U.: Oscillations and variability in the p53 system. Mol. Systems Biol. 2 (2006)
Goldbeter, A.: Computational approaches to cellular rhythms. Nature 420, 238–245 (2002)
Gordon, K.E., Van Leeuwen, I.M.M., Lain, S., Chaplain, M.A.J.: Spatio-temporal modelling of the p53-mdm2 oscillatory system. Math. Model. Nat. Phenom. 4, 97–116 (2009)
Haupt, Y., Maya, R., Kazaz, A., Oren, M.: Mdm2 promotes the rapid degradation of p53. Nature 387, 296–299 (1997)
Hirata, H., Yoshiura, S., Ohtsuka, T., Bessho, Y., Harada, T., Yoshikawa, K., Kageyama, R.: Oscillatory expression of the Bhlh factor Hes1 regulated by a negative feedback loop. Science 298, 840–843 (2002)
Horvath, G., Dini, P.: Lie Group Analysis of p53-mdm3 Pathway. In: Proceedings of the 3rd OPAALS International Conference, Aracaju, Sergipe, Brazil, March 22-23 (2010)
Krishna, S., Jensen, M.H., Sneppen, K.: Minimal model of spiky oscillations in NF-KB. Proc. Natl. Acad. Sci. USA 103, 10840–10845 (2006)
Kruse, J.P., Gu, W.: Modes of p53 regulation. Cell 137, 609–622 (2009)
Lahav, G.: Oscillations by the p53-mdm2 feedback loop. Adv. Exp. Med. Biol. 641, 28–38 (2008)
Lahav, G., Rosenfield, N., Sigal, A., Geva-Zatorsky, N., Levine, A.J., Elowitz, M.B., Alon, U.: Dynamics of the p53-mdm2 feedback loop in individual cells. Nat. Gen. 36, 147–150 (2004)
Lane, D.P.: p53, guardian of the genome. Nature 358, 15–16 (1992)
Lev Bar-Or, R., Maya, R., Segel, L.A., Alon, U., Levine, A.J., Oren, M.: Generation of oscillations by the p53-mdm2 feedback loop: a theoretical and experimental study. Proc. Natl. Acad. Sci. USA 97, 11250–11255 (2000)
Levine, H.A., Smiley, M.W., Tucker, A.L., Nilsen-Hamilton, M.: A mathematical model for the onset of avascular tumor growth in response to the loss of p53 function. Cancer Informatics 2, 163–188 (2006)
Ma, L., Wagner, J., Rice, J.J., Hu, W., Levine, A.J., Stolovitzky, G.A.: A plausible model for the digital response of p53 to dna damage. Proc. Natl. Acad. Sci. USA 102, 14266–14271 (2005)
Mihalas, G.I., Simon, Z., Balea, G., Popa, E.: Possible oscillatory behaviour in p53-mdm2 interaction computer simulation. J. Biol. Syst. 8, 21–29 (2000)
Monk, N.A.M.: Oscillatory expression of hes1, p53, and NF-KB driven by transcriptional time delays. Curr. Biol. 13, 1409–1413 (2003)
Nelson, D.E., Ihekwaba, A.E., Elliott, M., Johnson, J.R., Gibney, C.A., Foreman, B.E., Nelson, G., See, V., Horton, C.A., Spiler, D.G., Edwards, S.W., McDowell, H.P., Unitt, J.F., Sullivan, E., Grimley, R., Benson, N., Broomhead, D., Kell, D.B., White, M.R.: Oscillations in NF-KB signaling control de dynamics of gene expression. Science 306, 704–708 (2004)
Ogunnaike, B.A.: Elucidating the digital control mechanism for dna damage repair with the p53-mdm2 system: single cell data analysis and ensemble modelling. J. R. Soc. Interface 3, 175–184 (2006)
Pigolotti, S., Krishna, S., Jensen, M.H.: Oscillation patterns in negative feedback loops. Proc. Natl. Acad. Sci. USA 104, 6533–6537 (2007)
Proctor, C.J., Gray, D.A.: Explaining oscillations and variability in the p53-mdm2 system. BMC Syst. Biol. 2, 75 (2008)
Puszynski, K., Hat, B., Lipniacki, T.: Oscillations and bistability in the stochastic model of p53 regulation. J. Theor. Biol. 254, 452–465 (2008)
Ribba, B., Colin, T., Schnell, S.: A multiscale mathematical model of cancer, and its use in analyzing irradiation therapies. Theor. Biol. Med. Model. 3, 7 (2006)
Shieh, S.Y., Ikeda, M., Taya, Y., Prives, C.: DNA damage-induced phosphorylation of p53 alleviates inhibition by mdm2. Cell 91, 325–334 (1997)
Srividya, J., Gopinathan, M.S., Schnells, S.: The effects of time delays in a phosphorylation-dephosphorylation pathway. Biophys. Chem. 125, 286–297 (2007)
Tiana, G., Jensen, M.H., Sneppen, K.: Time delay as a key to apoptosis induction in the p53 network. Eur. Phys. J. B 29, 135–140 (2002)
Tiana, G., Krishna, S., Pigolotti, S., Jensen, M.H., Sneppen, K.: Oscillations and temporal signalling in cells. Phys. Biol. 4, R1–R17 (2007)
Tigges, M., Marquez-Lago, T.T., Stelling, J., Fussenegger, M.: A tunable synthetic mammalian oscillator. Nature 457, 309–312 (2009)
Vogelstein, B., Lane, D.P., Levine, A.J.: Surfing the p53 network. Nature 408, 307–310 (2007)
Wagner, J., Ma, L., Rice, J.J., Hu, W., Levine, A.J., Stolovitzky, G.A.: P53-mdm2 loop controlled by a balance of its feedback strength and effective dampening using atm and delayed feedback. IEE Proc. Syst. Biol. 152, 109–118 (2005)
Wawra, C., Kuhl, M., Kestler, H.A.: Extended analyses of the wntβ-cateni pathway: robustness and oscillatory behaviour. FEBS Lett. 581, 4043–4048 (2007)
Zauberman, A., Flusberg, D., Haupt, Y., Barak, Y., Oren, M.: A functional p53-response intronic promoter is contained within the human mdm2 gene. Nucleic Acids Res. 23, 2584–2592 (1995)
Zhang, T., Brazhnik, P., Tyson, J.J.: Exploring mechanisms of DNA damage response: p53 pulses and their possible relevance to apoptosis. Cell Cycle 6, 85–94 (2007)
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 ICST Institute for Computer Science, Social Informatics and Telecommunications Engineering
About this paper
Cite this paper
van Leeuwen, I.M.M., Sanders, I., Staples, O., Lain, S., Munro, A.J. (2010). Numerical and Experimental Analysis of the p53-mdm2 Regulatory Pathway. In: Antonio Basile Colugnati, F., Lopes, L.C.R., Barretto, S.F.A. (eds) Digital Ecosystems. OPAALS 2010. Lecture Notes of the Institute for Computer Sciences, Social Informatics and Telecommunications Engineering, vol 67. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-14859-0_20
Download citation
DOI: https://doi.org/10.1007/978-3-642-14859-0_20
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-14858-3
Online ISBN: 978-3-642-14859-0
eBook Packages: Computer ScienceComputer Science (R0)