Cellular stress responses permit cells to survive both chemical and physical stresses and may limit the sensitivity of tumor cells to Therapy. Heat shock factor 1 (HSF1) is an important regulator of stress responses and is the activator for transcription of the heat shock genes. In this study, we will explore a recently discovered property in HSF1 of widespread transcriptional repression of non-HSP genes including cytokine and mammalian immediate early genes. Through characterization of genes repressed by HSF1 and investigation of underlying molecular mechanisms, we will evaluate the role of repression in the function of HSF1 as a molecular coordinator of the stress response and the potential of this property in cancer treatment.
We aim to examine classes of genes repressed by HSF1 based on functional criteria or on differences in structures and sequences of target promoters. Our intention is to determine the ubiquity of HSF1 mediated repression, its investigating HSF1 binding and functional interaction with DNA sequences and proteins on target promoters, we will examine the molecular mechanisms of repression by HSF-1. We will study the stage of transcriptional activation at which HSF1 acts and the critical protein or DNA partners that mediate repression. This will be aided by mapping the domains within HSF1 that mediate repression and studying the interactions of repression and sequences with transcriptional machinery. We will next examine the regulation of repression under control and stress conditions and the discrimination mechanisms involved in selecting whether a promoter is repressed or activated by HSF1. Finally we examine the place of gene repression by HSF1 in the stress response and the utility of specific HSF1 inducers and accompanying gene repression in cancer therapy.
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