The stress response is an evolutionary conserved cellular response mechanism characterized by the enhanced synthesis and accumulation of heat shock proteins (Hsps). Hsps associate with key components of the signaling pathways that control cell growth and development. The level of Hsps is critical since variations in the level of Hsps' expression result in aberrant growth, developmental defects and cell death. The stress-inducible expression of Hsps' encoding genes is regulated by a family of heat shock transcription factors (Hsfs). Hsf1 is the major stress-responsive family member and during its cycle of activation and inactivation undergoes complex modifications such as phosphorylation and association with number of regulatory proteins. Phosphorylation of evolutionary conserved serine residues S303 and S307 and association with Hsf binding protein 1 (Hsbp1), repress Hsf1 activity. The significance of having an evolutionary conserved Hsf1 in vertebrates has been tested through the disruption of the hsf1 gene in the mouse. Studies of the mutant mouse reveal that hsf1 plays a critical role in maintenance of essential cellular functions and as an anti-apoptotic protein. In this grant application, to continue our efforts to understand the role of phosphorylation on Hsf1 activity and function, and to determine the roles of Hsbp1, which is an Hsf1 interacting protein, in regulating Hsf1 activity, we have generated a mutant mouse model where the serine residues S303/S307 have been replaced by alanine residues (S303A/S307A), and we have disrupted the hsbp1 gene in mice. These mouse models, in addition to hsf1-deficient mice we already have generated, will be used to understand how manipulation of Hsf1 levels and activity controls cellular growth or stress response. We propose the following specific aims: I. To identify the signaling networks involved in Hsf1 regulation and the consequence of phosphorylation on Hsf1 activity, II. To determine the function of Hsbp1 in controlling Hsf1 transcriptional activity in vivo, and III. To characterize the physiological role of Hsf1 in regulation of the stress response and apoptosis.
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