Control Strategies for the Regulation of the Eukaryotic Heat Shock Response
Elevated temperatures cause proteins in living cells to misfold. They start forming larger and larger aggregates that can eventually lead to the cell’s death. The heat shock response is an evolutionary well conserved cellular response to massive protein misfolding and it is driven by the need to keep the level of misfolded proteins under control. We consider in this paper a recently proposed new molecular model for the heat shock response in eukaryotes, consisting of a temperature-induced activation mechanism, chaperoning of misfolded proteins and self-regulation of the chaperon synthesis. We take in this paper a control driven approach to studying this regulatory network. We modularize the network by identifying its main functional modules. We distinguish three main feedback loops. The main question we are addressing is why is this level of complexity needed for implementing what could in principle also be achieved with an open-loop design. We answer the question by comparing the numerical behavior of various knockdown mutants where one or more feedback loops are missing. We also discuss a new approach for a biologically-unbiased model comparison.
KeywordsHeat Shock Reference Model Misfolded Protein Heat Shock Response Heat Shock Factor
Unable to display preview. Download preview PDF.
- 2.Chen, W.W., Schoeberl, B., Jasper, P.J., Niepel, M., Nielsen, U.B., Lauffenburger, D.A., Sorger, P.K.: Input output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data. Molecular Systems Biology 5, 239Google Scholar
- 4.Guldberg, C.M., Waage, P.: Studies Concerning Affinity. C. M. Forhandlinger: Videnskabs-Selskabet i Christiana 35 (1864)Google Scholar
- 6.Hawkins, B.A., Cornell, H.V. (eds.): Theoretical Approaches to Biological Control. Cambridge University Press, Cambridge (1999)Google Scholar
- 11.Petre, I., Mizera, A., Hyder, C.L., Mikhailov, A., Eriksson, J.E., Sistonen, L., Back, R.-J.: A new mathematical model for the heat shock response. In: Kok, J. (ed.) Algorithmic bioprocesses. Natural Computing. Springer, Heidelberg (2008)Google Scholar
- 12.Petre, I., Hyder, C.L., Mizera, A., Mikhailov, A., Eriksson, J.E., Sistonen, L., Back, R.-J.: A simple mathematical model for the eukaryotic heat shock response (submitted, 2009)Google Scholar