Heat Shock Transcription Factor Function and Regulation

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DESCRIPTION (provided by applicant): All organisms and cells are exposed to stressful conditions, whether a consequence of elevations in environmental temperatures or toxic compounds, in response to reactive oxygen species generated through normal mitochondrial respiration, pharmacological agents, infection and inflammation, normal cell growth and division or other physiological or pathophysiological conditions. Exposure to stress results in perturbations in the cell cycle, dramatic reprogramming of gene expression and cellular homeostatic controls and in the unfolding and deposition of proteins. The inability to mount appropriate stress responses is associated with stroke and ischemia-reperfusion injury, cancer, aging, defects in organismal growth, development, infertility and in neurodegenerative diseases characterized by protein aggregation and deposition. Eukaryotic cells respond to stress conditions by inducing the synthesis of heat shock proteins (Hsps), which function in protein folding, trafficking, degradation and in the maturation and activation of signal transduction proteins and transcription factors. In this application we outline studies on the induction of Hsp expression by Heat Shock Transcription Factors (HSFs), stress-responsive transcription factors conserved from yeast to humans. First, the mechanisms by which mammalian HSF1 senses stress will be elucidated. Secondly, cellular factors that modulate mammalian HSF1 stress activation will be identified and their mechanisms of action ascertained. Third, a genome wide identification of yeast HSF target genes will be carried out. Yeast HSF target gene regulatory networks will be analyzed as a paradigm for understanding the broad biological significance of the HSF stress response, and these studies will be extrapolated to the identification of mammalian HSF1 target genes. Hsps function to protect organisms from stroke and ischemia reperfusion injury, and activation of HSF1 has been shown to suppress protein aggregation similar to that found in neurodegenerative disease. Therefore, understanding how HSF1 senses and responds to stress, and the target genes activated during stress, have important