The heat shock transcription factor (HSF) is a transcriptional regulator whose response to heat shock and other stresses is to activate the expression of the heat shock proteins, a set of proteins that have critical constitutive and protective functions. Heat shock proteins also play multiple roles in several disease states, including cancer, cardiovascular problems, and neurodegenerative conditions involving protein aggregation. The ability to control the expression of heat shock proteins under different conditions could have profound effects on these disease states. Therefore, it has become important to understand how the activity of HSF is regulated, so that we can learn how to control its activity. HSF has a low level of activity prior to stress and acquires a high level of transcriptional activity after stress. The modulation of HSF's activity likely involves other regulatory proteins, post-translational modifications, and cellular localization. Of interest to this proposal is the fact that mutations and/or deletions within HSF can cause it to become constitutively active. Therefore, it is the integrity of the HSF structure that appears to be most critical for regulating its activity.
The specific aims of this proposal focus on the DNA-binding and trimerization domains, two domains for which much is known about the structure and function. Previous structural and genetic studies will guide the choice of HSF mutants to use to test hypotheses as to whether charge, surface topology, thermal stability, and/or overall structure are critical for the normal regulation of HSF's transcriptional activity. The ability of these mutant HSFs to differentially activate different heat shock promoters and to be differentially induced by different stresses will be also analyzed. These studies will deepen our understanding of how the structure of HSF relates to its activity and will help lead to the long term goal of being able to manipulate HSF's function in order to take advantage of its protective role.
Showing the most recent 10 out of 20 publications
