ROLE OF HSF2 IN THE STRESS RESPONSE TO HYPERTHERMIA

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The sensitivity of cancer cells to cytotoxic therapy is resisted by the expression of stress responses such as the heat shock response. We aim to investigate the consequences of novel finding made in our laboratory indicating that the transcription factor heat shock factor 2 (HSF2) is activated by stress and play a role in mediating the resistance of cells to hyperthermia and other treatments. We aim to delineate the role of HSF2 in the response of cells to the stresses of cancer therapy and the tumor microenvironment. Our hypothesis is that HSF2 acts cooperatively with other stress responsive factors including HSF1 to regulate HSP gene transcription and to induce a coordinate stress response that results in the expression of molecular chaperones. We will first determine the molecular mechanisms by which HSF2 is recruited to stress-inducible promoters, binds DNA, interacts with other factors and activates transcription. We aim to identify the functional domains in HSF2 that regulate the activity of target promoters and to determine the mechanisms of interaction between HSF family members. Our hypothesis is that complex formation between HSF family members regulates the trans- activation of stress-responsive promoters. We will then analyze the role of HSF2 within the stress response in human malignant cells. Using dominant negative and constitutively activated constructs prepared during the first phase of the project, we propose to determine the relative roles of HSF1 and HSF2 in resistance to apoptosis and clonogenic cell death and to uncover mechanisms of HSF activation in malignant cells.