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Biophys. J. BioFAST: First Published December 30, 2004. doi:10.1529/biophysj.104.055301
© 2004 by the Biophysical Society.

A more recent version of this article appeared on March 1, 2005.
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BIOPHYSICAL THEORY AND MODELING

Mathematical modeling of the eukaryotic heat shock response: Dynamics of the hsp70 promoter

Theodore R. Rieger 1, Richard I. Morimoto 1 and Vassily Hatzimanikatis 1*

1 Northwestern University

* To whom correspondence should be addressed. E-mail: vassily{at}northwestern.edu.

Submitted on October 27, 2004
Revised on November 22, 2004
Accepted on 20 December 2004


  Abstract
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.

Key Words: Genetic network, HSF1 phosphorylation, HSF1 regulation, Nonlinear dynamics, Sensitivity analysis, Transcriptional regulation




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Copyright © 2004 by the Biophysical Society.