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Mathematical Modeling of the Eukaryotic Heat-Shock Response: Dynamics of the hsp70 Promoter

Theodore R. Rieger ^*, Richard I. Morimoto  and Vassily Hatzimanikatis ^*

^* Departments of Chemical and Biological Engineering, Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois

Correspondence: Address reprint requests to Prof. Vassily Hatzimanikatis, 2145 Sheridan Rd., E136, Evanston, IL 60208-3120. Tel.: 847-491-5357; Fax: 847-491-3728; E-mail: vassily{at}northwestern.edu.

The heat-shock response in humans and other eukaryotes is a highly conserved genetic network that coordinates the cellular response to protein damage and is essential for adaptation and survival of the stressed cell. It involves an immediate and transient activation of heat-shock transcription factor-1 (HSF1) which results in the elevated expression of genes encoding proteins important for protein homeostasis including molecular chaperones and components of the protein degradative machinery. We have developed a mathematical model of the critical steps in the regulation of HSF1 activity to understand how chronic exposure to a stress signal is converted into specific molecular events for activation and feedback regulated attenuation of HSF1. The model is utilized to identify the most sensitive steps in HSF1 activation and to evaluate how these steps affect the expression of molecular chaperones. This analysis allows the formulation of hypotheses about the differences between the heat-shock responses in yeast and humans and generates a model with predictive abilities relevant to diseases associated with the accumulation of damaged and aggregated proteins including cancer and neurodegenerative diseases.

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