title: Heat shock transcription factor 1 is activated as a consequence of lymphocyte activation and regulates a major proteostasis network in T cells critical for cell division during stress.
abstract: Heat shock transcription factor 1 (HSF1) is a major transcriptional regulator of the heat shock response in eukaryotic cells. HSF1 is evoked in response to a variety of cellular stressors, including elevated temperatures, oxidative stress, and other proteotoxic stressors. Previously, we demonstrated that HSF1 is activated in naive T cells at fever range temperatures (39.5°C) and is critical for in vitro T cell proliferation at fever temperatures. In this study, we demonstrated that murine HSF1 became activated to the DNA-binding form and transactivated a large number of genes in lymphoid cells strictly as a consequence of receptor activation in the absence of apparent cellular stress. Microarray analysis comparing HSF1(+/+) and HSF1(-/-) gene expression in T cells activated at 37°C revealed a diverse set of 323 genes significantly regulated by HSF1 in nonstressed T cells. In vivo proliferation studies revealed a significant impairment of HSF1(-/-) T cell expansion under conditions mimicking a robust immune response (staphylococcal enterotoxin B-induced T cell activation). This proliferation defect due to loss of HSF1 is observed even under nonfebrile temperatures. HSF1(-/-) T cells activated at fever temperatures show a dramatic reduction in cyclin E and cyclin A proteins during the cell cycle, although the transcription of these genes was modestly affected. Finally, B cell and hematopoietic stem cell proliferation from HSF1(-/-) mice, but not HSF1(+/+) mice, were also attenuated under stressful conditions, indicating that HSF1 is critical for the cell cycle progression of lymphoid cells activated under stressful conditions.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky School of Medicine, Lexington, KY 40536.
authors.forename: Siva K
authors.initials: SK
authors.lastname: Gandhapudi
authors.forename: Patience
authors.initials: P
authors.lastname: Murapa
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Threlkeld
authors.forename: Martin
authors.initials: M
authors.lastname: Ward
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Sarge
authors.forename: Charles
authors.initials: C
authors.lastname: Snow
authors.forename: Jerold G
authors.initials: JG
authors.lastname: Woodward
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D049109:Cell Proliferation; D002478:Cells, Cultured; D019925:Cyclin A / Q000096:biosynthesis; D019927:Cyclin E / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004768:Enterotoxins / Q000276:immunology; D005334:Fever / Q000276:immunology; D005786:Gene Expression Regulation; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D019925:Cyclin A; D019927:Cyclin E; D004268:DNA-Binding Proteins; D004768:Enterotoxins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C031818:enterotoxin B, staphylococcal
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