All organisms are constantly exposed to stressful conditions as a consequence of normal cell growth and division, infection, exposure to pharmacological agents, environmental insults or unregulated cell growth in the cancerous state. Heat Shock Factors (HSF) are a class of highly conserved transcription factors which sense and respond to a wide variety of cellular stresses to regulate the expression of genes that are vital to survival during stress and for the establishment of normal cellular homeostatic controls. HSF regulates the expression of genes encoding protein chaperones, which play pivotal roles in protein folding, maturation, targeting and the activation of key cellular growth control proteins, as well as genes encoding proto-oncoproteins, pain receptors, cytokines and immune surveillance molecules. In this application we describe experiments with the overall objective of understanding how HSF proteins sense distinct stresses to activate gene expression, using both yeast and human cells as model systems. First, the mechanisms by which yeast cells sense growth control signals through glucose, and transmit this information to activate HSF function, will be explored through genetic, biochemical and molecular biology approaches. Secondly, using both yeast cells and human cells, as well as in vitro techniques, the mechanisms whereby cells retain human HSF proteins in an inactive form, and respond to stress signals to activate HSF molecules, will be investigated. Third, the molecular mechanisms by which distinct human HSF isoforms activate distinct target genes, and the identification of these genes, will be investigated in both yeast and human cells. The experiments described in this proposal will provide insight into how this highly conserved class of stress- responsive transcription factors sense and respond to stresses that occur during normal growth, and disease states, to maintain cellular regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM059911-05
Application #
6865312
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Anderson, James J
Project Start
1999-08-01
Project End
2004-03-31
Budget Start
2003-12-16
Budget End
2004-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$91,963
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; 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
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
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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