? All organisms and cells are exposed to stressful conditions, whether a consequence of elevations in environmental temperatures or toxic compounds, in response to reactive oxygen species generated through normal mitochondrial respiration, pharmacological agents, infection and inflammation, normal cell growth and division or other physiological or pathophysiological conditions. Exposure to stress results in perturbations in the cell cycle, dramatic reprogramming of gene expression and cellular homeostatic controls and in the unfolding and deposition of proteins. The inability to mount appropriate stress responses is associated with stroke and ischemia-reperfusion injury, cancer, aging, defects in organismal growth, development, infertility and in neurodegenerative diseases characterized by protein aggregation and deposition. Eukaryotic cells respond to stress conditions by inducing the synthesis of heat shock proteins (Hsps), which function in protein folding, trafficking, degradation and in the maturation and activation of signal transduction proteins and transcription factors. In this application we outline studies on the induction of Hsp expression by Heat Shock Transcription Factors (HSFs), stress-responsive transcription factors conserved from yeast to humans. First, the mechanisms by which mammalian HSF1 senses stress will be elucidated. Secondly, cellular factors that modulate mammalian HSF1 stress activation will be identified and their mechanisms of action ascertained. Third, a genome wide identification of yeast HSF target genes will be carried out. Yeast HSF target gene regulatory networks will be analyzed as a paradigm for understanding the broad biological significance of the HSF stress response, and these studies will be extrapolated to the identification of mammalian HSF1 target genes. Hsps function to protect organisms from stroke and ischemia reperfusion injury, and activation of HSF1 has been shown to suppress protein aggregation similar to that found in neurodegenerative disease. Therefore, understanding how HSF1 senses and responds to stress, and the target genes activated during stress, have important ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059911-07
Application #
6870185
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Anderson, James J
Project Start
1999-08-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
7
Fiscal Year
2005
Total Cost
$308,000
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Neef, Daniel W; Jaeger, Alex M; Thiele, Dennis J (2013) Genetic selection for constitutively trimerized human HSF1 mutants identifies a role for coiled-coil motifs in DNA binding. G3 (Bethesda) 3:1315-24
Neef, Daniel W; Jaeger, Alex M; Thiele, Dennis J (2011) Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat Rev Drug Discov 10:930-44
Neef, Daniel W; Turski, Michelle L; Thiele, Dennis J (2010) Modulation of heat shock transcription factor 1 as a therapeutic target for small molecule intervention in neurodegenerative disease. PLoS Biol 8:e1000291
Neef, Daniel W; Thiele, Dennis J (2009) Enhancer of decapping proteins 1 and 2 are important for translation during heat stress in Saccharomyces cerevisiae. Mol Microbiol 73:1032-42
Park, Kyung-Won; Hahn, Ji-Sook; Fan, Qing et al. (2006) De novo appearance and ""strain"" formation of yeast prion [PSI+] are regulated by the heat-shock transcription factor. Genetics 173:35-47
Hahn, Ji-Sook; Neef, Daniel W; Thiele, Dennis J (2006) A stress regulatory network for co-ordinated activation of proteasome expression mediated by yeast heat shock transcription factor. Mol Microbiol 60:240-51
Anckar, Julius; Hietakangas, Ville; Denessiouk, Konstantin et al. (2006) Inhibition of DNA binding by differential sumoylation of heat shock factors. Mol Cell Biol 26:955-64
Hahn, Ji-Sook; Hu, Zhanzhi; Thiele, Dennis J et al. (2004) Genome-wide analysis of the biology of stress responses through heat shock transcription factor. Mol Cell Biol 24:5249-56
Hahn, Ji-Sook; Thiele, Dennis J (2004) Activation of the Saccharomyces cerevisiae heat shock transcription factor under glucose starvation conditions by Snf1 protein kinase. J Biol Chem 279:5169-76
Ahn, Sang-Gun; Thiele, Dennis J (2003) Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev 17:516-28

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