Gene Repression by HSF1 during hyperthermia and stresses

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DESCRIPTION (provided by applicant): Heat shock results in a dramatic. shift in gene expression from genes involved in growth and differentiated function to stress gene expression. We have recently discovered that heat shock factor 1 (HSF1), the molecular coordinator of the heat shock response is a potent repressor of (non-heat shock) gene transcription. We aim to determine the role of gene repression by HSF1 in the immune response, the regulation of proliferation and in cellular responses to stress. By studying the profile of genes repressed by HSF1 and the underlying molecular mechanisms, we aim to determine the gene repression role of HSF1 in the immune response and the cellular stress response. There are three specific aims, which include: Firstly, we will examine the molecular mechanisms underlying repression of interleukin 1 and c-fos by HSF1. 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 comprehensive genetic mapping of the domains within HSF1 that mediate repression and their interactions with the transcriptional machinery of target cells. In the second aim, we will study the intracellular regulation of gene repression by HSF1. We will investigate a number of highly-conserved phosphorylation sites within HSF1 that regulate repression and will examine the functional role of phosphorylation in the control of gene expression/repression by HSF1. Finally, we will investigate the physiological role of gene repression in a number of systems, including the immune response and the cellular stress response. This involves identifying genes induced during monocyte activation and mitogenic stimulation that are repressed by HSF1. We will use high density gene microarray expression profiling to identify global changes in gene expression/repression during HSF1 activation. Further experiments will address the place of gene repression by HSF1 in the stress response and is potential role in hyperthermia. Dominant negative inhibitors of HSF1 repression have been identified in this study and they will be used in transfected cells to study the cellular consequences of gene repression by HSF 1.