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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 mol. chaperones and components of the protein degradative machinery. The authors have developed a math. model of the crit. steps in the regulation of HSF1 activity to understand how chronic exposure to a stress signal is converted into specific mol. 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 mol. chaperones. This anal. 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 assocd. with the accumulation of damaged and aggregated proteins including cancer and neurodegenerative diseases. [on SciFinder (R)]