The Community for Technology Leaders
RSS Icon
Issue No.05 - Sept.-Oct. (2012 vol.9)
pp: 1326-1337
Eugen Czeizler , Dept. of Inf. & Comput. Sci., Aalto Univ., Aalto, Finland
Vladimir Rogojin , Fac. of Med., Helsinki Univ., Helsinki, Finland
Ion Petre , Dept. of Inf. Technol., Abo Akademi Univ., Turku, Finland
The heat shock response is a well-conserved defence mechanism against the accumulation of misfolded proteins due to prolonged elevated heat. The cell responds to heat shock by raising the levels of heat shock proteins (hsp), which are responsible for chaperoning protein refolding. The synthesis of hsp is highly regulated at the transcription level by specific heat shock (transcription) factors (hsf). One of the regulation mechanisms is the phosphorylation of hsf's. Experimental evidence shows a connection between the hyper-phosphorylation of hsfs and the transactivation of the hsp-encoding genes. In this paper, we incorporate several (de)phosphorylation pathways into an existing well-validated computational model of the heat shock response. We analyze the quantitative control of each of these pathways over the entire process. For each of these pathways we create detailed computational models which we subject to parameter estimation in order to fit them to existing experimental data. In particular, we find conclusive evidence supporting only one of the analyzed pathways. Also, we corroborate our results with a set of computational models of a more reduced size.
proteins, biothermics, cellular biophysics, genetics, molecular biophysics, parameter estimation, parameter estimation, phosphorylation, heat shock factor, heat shock response, well-conserved defence mechanism, misfolded protein accumulation, cell, chaperoning protein refolding, specific heat shock factors, transcription factors, hsp-encoding genes, computational models, Computational modeling, Heating, Electric shock, Proteins, Biological system modeling, Kinetic theory, Numerical models, quantitative refinement., Simulation, modeling, computing methodologies, biology and genetics, computer applications, heat shock response, protein phosphorylation
Eugen Czeizler, Vladimir Rogojin, Ion Petre, "The Phosphorylation of the Heat Shock Factor as a Modulator for the Heat Shock Response", IEEE/ACM Transactions on Computational Biology and Bioinformatics, vol.9, no. 5, pp. 1326-1337, Sept.-Oct. 2012, doi:10.1109/TCBB.2012.66
[1] R.I. Morimoto, "Cells in Stress: Transcriptional Activation of Heat Shock Genes," Science, vol. 259, pp. 1409-1410, 1993.
[2] M. Jaattela, "Escaping Cell Death: Survival Proteins in Cancer," Experimental Cell Research, vol. 248, pp. 30-43, 1999.
[3] B. Alberts, A. Johnson, J. Lewis, M. Raff, D. Bray, K. Hopkin, K. Roberts, and P. Walter, Essential Cell Biology, second ed., Garland Science/Taylor & Francis Group, 2003.
[4] C.L. Masters, G. Simms, N.A. Weinman, G. Multhaup, B.L. McDonald, and K. Beyreuther, "Amyloid Plaque Core Protein in Alzheimer Disease and Down Syndrome," Proc. Nat'l Academy of Sciences USA, vol. 82, pp. 4245-4249, 1985.
[5] E. Scherzinger, R. Lurz, M. Turmaine, L. Mangiarini, B. Hollenbach, R. Hasenbank, G.P. Bates, S.W. Davies, H. Lehrach, and E.E. Wanker, "Huntingtin-Encoded Polyglutamine Expansions form Amyloid-Like Protein Aggregates in Vitro and in Vivo," Cell, vol. 90, pp. 549-558, 1997.
[6] M.P. Kline and R.I. Morimoto, "Repression of the Heat Shock Factor 1 Transcriptional Activation Domain is Modulated by Constitutive Phosphorylation," Moleculer and Cellular Biology, vol. 17, pp. 2107-2115, 1997.
[7] A. Peper, C.A. Grimbergen, J.A. Spaan, J.E. Souren, and R. van Wijk, "A Mathematical Model of the hsp70 Regulation in the Cell," Int J. Hyperthermia, vol. 14, pp. 97-124, 1998.
[8] T.R. Rieger, R.I. Morimoto, and V. Hatzimanikatis, "Mathematical Modeling of the Eukaryotic Heat-Shock Response: Dynamics of the hsp70 Promoter," Biophysical J., vol. 88, no. 3, pp. 1646-1658, 2005.
[9] A.La Terza, G. Papa, C. Miceli, and P. Luporini, "Divergence Between two Antarctic Species of the Ciliate Euplotes, E. Focardii and E. Nobilii, in the Expression of Heat-Shock Protein 70 Genes," Moleculer Ecology, vol. 10, pp. 1061-1067, 2001.
[10] G.E. Hofmann, B.A. Buckley, S. Airaksinen, J.E. Keen, and G.N. Somero, "Heat-Shock Protein Expression is Absent in the Antarctic Fish Trematomus Bernacchii (Family Nototheniidae)," J. Experimental Biology, vol. 203, pp. 2331-2339, 2000.
[11] M.S. Clark, K.P. Fraser, and L.S. Peck, "Antarctic Marine Molluscs Do Have an HSP70 Heat Shock Response," Cell Stress and Chaperones, vol. 13, pp. 39-49, 2008.
[12] H.H. Kampinga, "Thermotolerance in Mammalian Cells. Protein Denaturation and Aggregation, and Stress Proteins," J. Cell Science, vol. 104, no. Pt 1, pp. 11-17, 1993.
[13] A.G. Pockley, "Heat Shock Proteins as Regulators of the Immune Response," Lancet, vol. 362, pp. 469-476, 2003.
[14] D.R. Ciocca and S.K. Calderwood, "Heat Shock Proteins in Cancer: Diagnostic, Prognostic, Predictive, and Treatment Implications," Cell Stress Chaperones, vol. 10, pp. 86-103, 2005.
[15] P. Workman and E. de Billy, "Putting the Heat on Cancer," Nature Medicine, vol. 13, pp. 1415-1417, 2007.
[16] P.K. Sorger, M.J. Lewis, and H.R. Pelham, "Heat Shock Factor is Regulated Differently in Yeast and Hela Cells," Nature, vol. 329, pp. 81-84, 1987.
[17] J.S. Larson, T.J. Schuetz, and R.E. Kingston, "Activation in Vitro of Sequence-Specific DNA Binding by a Human Regulatory Factor," Nature, vol. 335, pp. 372-375, 1988.
[18] P.K. Sorger, "Yeast Heat Shock Factor Contains Separable Transient and Sustained Response Transcriptional Activators," Cell, vol. 62, pp. 793-805, 1990.
[19] C.I. Holmberg, V. Hietakangas, A. Mikhailov, J.O. Rantanen, M. Kallio, A. Meinander, J. Hellman, N. Morrice, C. MacKintosh, R.I. Morimoto, J.E. Eriksson, and L. Sistonen, "Phosphorylation of Serine 230 Promotes Inducible Transcriptional Activity of Heat Shock Factor 1," EMBO J., vol. 20, pp. 3800-3810, 2001.
[20] I. Petre, A. Mizera, C.L. Hyder, A. Mikhailov, J.E. Eriksson, L. Sistonen, and R.-J. Back, "A New Mathematical Model for the Heat Shock Response," Algorithmic Bioprocesses, ser. Natural Computing Series, A. Condon, D. Harel, J.N. Kok, A. Salomaa, and E. Winfree, eds., pp. 411-425, Springer, 2009.
[21] I. Petre, A. Mizera, C.L. Hyder, A. Meinander, A. Mikhailov, R.I. Morimoto, L. Sistonen, J.E. Eriksson, and R.-J. Back, "A Simple Mass-Action Model for the Eukaryotic Heat Shock Response and its Mathematical Validation," Natural Computing, vol. 10, no. 1, pp. 595-612, 2011.
[22] K. Laidler, Chemical Kinetics, third ed. Benjamin-Cummings, 1997.
[23] J. Lepock, H. Frey, and K. Ritchie, "Protein Denaturation in Intact Hepatocytes and Isolated Cellular Organelles During Heat Shock," J. Cell Biology, vol. 122, no. 6, pp. 1267-76, 1993.
[24] V. Hietakangas, J.K. Ahlskog, A.M. Jakobsson, M. Hellesuo, N.M. Sahlberg, C.I. Holmberg, A. Mikhailov, J.J. Palvimo, L. Pirkkala, and L. Sistonen, "Phosphorylation of Serine 303 is a Prerequisite for the Stress-Inducible SUMO Modification of Heat Shock Factor 1," Moleculer and Cellular Biology, vol. 23, pp. 2953-2968, 2003.
[25] C.I. Holmberg, S.E. Tran, J.E. Eriksson, and L. Sistonen, "Multisite Phosphorylation Provides Sophisticated Regulation of Transcription Factors," Trends Biochemical Sciences, vol. 27, pp. 619-627, 2002.
[26] L. Pirkkala, P. Nykanen, and L. Sistonen, "Roles of the Heat Shock Transcription Factors in Regulation of the Heat SHock Response and Beyond," FASEB J., vol. 15, pp. 1118-1131, 2001.
[27] W.W. Chen, B. Schoeberl, P.J. Jasper, M. Niepel, U.B. Nielsen, D.A. Lauffenburger, and P.K. Sorger, "Input-Output Behavior of ErbB Signaling Pathways as Revealed by a Mass Action Model Trained against Dynamic Data," Moleculer Systems Biology, vol. 5, p. 239, 2009.
[28] H.C. Edwards and D.E. Penney, Differential Equations: Computing and Modeling, third ed. Prentice Hall, 2003.
[29] E. Czeizler, V. Rogojin, and I. Petre, "The Phosphorylation of the Heat Shock Factor as a Modulator for the Heat Shock Response: Computational Models,", 2012.
[30] S. Hoops, S. Sahle, R. Gauges, C. Lee, J. Pahle, N. Simus, M. Singhal, L. Xu, P. Mendes, and U. Kummer, "COPASI-a Complex PAthway SImulator," Bioinformatics, vol. 22, pp. 3067-3074, 2006.
[31] V. Danos, J. Feret, W. Fontana, R. Harmer, and J. Krivine, "Rule-Based Modelling and Model Perturbation," Trans. Computational Systems Biology XI, vol. 5750, pp. 116-137, 2009.
[32] R. Harmer, "Rule-Based Modelling and Tunable Resolution," Proc. DCM, pp. 65-72, 2009.
[33] E. Czeizler, E. Czeizler, B. Iancu, and I. Petre, "Quantitative Model Refinement as a Solution to the Combinatorial State Explosion of Biomodels," Proc. Second Int'l Workshop Static Analysis and Systems Biology (SASB '11), and TUCS Technical Report 1015, 2011.
[34] A. Mizera, E. Czeizler, and I. Petre, "Self-Assembly Models of Variable Resolution," Trans. Computational Systems Biology, 2012.
[35] S.M. Baker, K. Schallau, and B.H. Junker, "Comparison of Different Algorithms for Simultaneous Estimation of Multiple Parameters in Kinetic Metabolic Models," J. Integrative Bioinformatics, vol. 7, no. 3, pp. 1-9, 2010.
[36] P. Mendes and D. Kell, "Non-Linear Optimization of Biochemical Pathways: Applications to Metabolic Engineering and Parameter Estimation," Bioinformatics, vol. 14, no. 10, pp. 869-883, 1998.
[37] C.G. Moles, P. Mendes, and J.R. Banga, "Parameter Estimation in Biochemical Pathways: A Comparison of Global Optimization Methods," Genome Research, vol. 13, no. 11, pp. 2467-2474, 2003.
[38] I.E. Grossmann, Global Optimization in Engineering Design. Kluwer Academic Publishers, 1996.
[39] R. Horst and H. Tuy, Global Optimization: Deterministic Approaches. Springer, 1990.
[40] M.M. Ali, C. Storey, and A. Torn, "Application of Stochastic Global Optimization Algorithms to Practical Problems 1," J. Optimization Theory and Applications, vol. 95, no. 3, pp. 545-563, 1997.
[41] C. Guus, E. Boender, and H. Romeijn, "Stochastic Methods," Handbook of Global Optimization. Kluwer Academic Publishers, 1995.
[42] M. Kühnel, L.S. Mayorga, T. Dandekar, J. Thakar, R. Schwarz, E. Anes, G. Griffiths, and J. Reich, "Modelling Phagosomal Lipid Networks that Regulate Actin Assembly," BMC Systems Biology, vol. 2, article 107, 2008.
[43] H. Câteau and S. Tanaka, "Kinetic Analysis of Multisite Phosphorylation Using Analytic Solutions to Michaelis-Menten Equations," J. Theoretical Biology, vol. 217, no. 1, pp. 1-14, 2002.
46 ms
(Ver 2.0)

Marketing Automation Platform Marketing Automation Tool