Targeted disruption of hsf1 leads to lack of thermotolerance and defines tissue-specific regulation for stress-inducible hsp molecular chaperones

Yan Zhang, Lei Huang, Jing Zhang, Dimitrios Moskofidis, Nahid F Mivechi

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109 Citations (Scopus)

Abstract

The rapid synthesis of heat shock proteins (Hsps) in cells subjected to environmental challenge is controlled by heat shock transcription factor-1 (Hsf1). Regulation of Hsps by Hsf1 is highly complex and, in the whole organism, remains largely unexplored. In this study, we have used mouse embryo fibroblasts and bone marrow progenitor cells from hsf1-/- mice as well as hsp70.3-lacZ knock-in mice bred on the hsf1 deficient genetic background (hsf1-/--hsp70.3+/--lacZ), to further elucidate the function of Hsf1 and its participation as a transcriptional activator of Hsp70 synthesis under normal or heat-induced stress conditions in vitro and in vivo. The results revealed that heat-induced Hsp70 expression in mouse tissue is entirely controlled by Hsf1, whereas its activity is not required for tissue-specific constitutive Hsp70 expression. We further demonstrate that Hsf1 is critical for maintaining cellular integrity after heat stress and that cells from hsf1-/- mice lack the ability to develop thermotolerance. This deficiency is explained by the elimination of stress-inducible Hsp70 and Hsp25 response in the absence of Hsf1 activity, leading to a lack of Hsp-mediated inhibition of apoptotic cell death via both caspase-dependent and caspase-independent pathways. The pivotal role of the Hsf1 transactivator in regulating rapid synthesis of Hsps as a critical cellular defense mechanism against environmental stress-induced damage is underlined.

Original languageEnglish (US)
Pages (from-to)376-393
Number of pages18
JournalJournal of cellular biochemistry
Volume86
Issue number2
DOIs
StatePublished - Jul 18 2002

Fingerprint

Molecular Chaperones
Heat-Shock Proteins
Tissue
Hot Temperature
Caspases
Trans-Activators
Cell death
Fibroblasts
heat shock transcription factor
Thermotolerance
Bone Marrow Cells
Bone
Cell Death
Stem Cells
Embryonic Structures

Keywords

  • Apoptosis
  • Gene disruption
  • Heat shock factor 1
  • Heat shock protein 70
  • Knock-in

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Targeted disruption of hsf1 leads to lack of thermotolerance and defines tissue-specific regulation for stress-inducible hsp molecular chaperones",
abstract = "The rapid synthesis of heat shock proteins (Hsps) in cells subjected to environmental challenge is controlled by heat shock transcription factor-1 (Hsf1). Regulation of Hsps by Hsf1 is highly complex and, in the whole organism, remains largely unexplored. In this study, we have used mouse embryo fibroblasts and bone marrow progenitor cells from hsf1-/- mice as well as hsp70.3-lacZ knock-in mice bred on the hsf1 deficient genetic background (hsf1-/--hsp70.3+/--lacZ), to further elucidate the function of Hsf1 and its participation as a transcriptional activator of Hsp70 synthesis under normal or heat-induced stress conditions in vitro and in vivo. The results revealed that heat-induced Hsp70 expression in mouse tissue is entirely controlled by Hsf1, whereas its activity is not required for tissue-specific constitutive Hsp70 expression. We further demonstrate that Hsf1 is critical for maintaining cellular integrity after heat stress and that cells from hsf1-/- mice lack the ability to develop thermotolerance. This deficiency is explained by the elimination of stress-inducible Hsp70 and Hsp25 response in the absence of Hsf1 activity, leading to a lack of Hsp-mediated inhibition of apoptotic cell death via both caspase-dependent and caspase-independent pathways. The pivotal role of the Hsf1 transactivator in regulating rapid synthesis of Hsps as a critical cellular defense mechanism against environmental stress-induced damage is underlined.",
keywords = "Apoptosis, Gene disruption, Heat shock factor 1, Heat shock protein 70, Knock-in",
author = "Yan Zhang and Lei Huang and Jing Zhang and Dimitrios Moskofidis and Mivechi, {Nahid F}",
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T1 - Targeted disruption of hsf1 leads to lack of thermotolerance and defines tissue-specific regulation for stress-inducible hsp molecular chaperones

AU - Zhang, Yan

AU - Huang, Lei

AU - Zhang, Jing

AU - Moskofidis, Dimitrios

AU - Mivechi, Nahid F

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N2 - The rapid synthesis of heat shock proteins (Hsps) in cells subjected to environmental challenge is controlled by heat shock transcription factor-1 (Hsf1). Regulation of Hsps by Hsf1 is highly complex and, in the whole organism, remains largely unexplored. In this study, we have used mouse embryo fibroblasts and bone marrow progenitor cells from hsf1-/- mice as well as hsp70.3-lacZ knock-in mice bred on the hsf1 deficient genetic background (hsf1-/--hsp70.3+/--lacZ), to further elucidate the function of Hsf1 and its participation as a transcriptional activator of Hsp70 synthesis under normal or heat-induced stress conditions in vitro and in vivo. The results revealed that heat-induced Hsp70 expression in mouse tissue is entirely controlled by Hsf1, whereas its activity is not required for tissue-specific constitutive Hsp70 expression. We further demonstrate that Hsf1 is critical for maintaining cellular integrity after heat stress and that cells from hsf1-/- mice lack the ability to develop thermotolerance. This deficiency is explained by the elimination of stress-inducible Hsp70 and Hsp25 response in the absence of Hsf1 activity, leading to a lack of Hsp-mediated inhibition of apoptotic cell death via both caspase-dependent and caspase-independent pathways. The pivotal role of the Hsf1 transactivator in regulating rapid synthesis of Hsps as a critical cellular defense mechanism against environmental stress-induced damage is underlined.

AB - The rapid synthesis of heat shock proteins (Hsps) in cells subjected to environmental challenge is controlled by heat shock transcription factor-1 (Hsf1). Regulation of Hsps by Hsf1 is highly complex and, in the whole organism, remains largely unexplored. In this study, we have used mouse embryo fibroblasts and bone marrow progenitor cells from hsf1-/- mice as well as hsp70.3-lacZ knock-in mice bred on the hsf1 deficient genetic background (hsf1-/--hsp70.3+/--lacZ), to further elucidate the function of Hsf1 and its participation as a transcriptional activator of Hsp70 synthesis under normal or heat-induced stress conditions in vitro and in vivo. The results revealed that heat-induced Hsp70 expression in mouse tissue is entirely controlled by Hsf1, whereas its activity is not required for tissue-specific constitutive Hsp70 expression. We further demonstrate that Hsf1 is critical for maintaining cellular integrity after heat stress and that cells from hsf1-/- mice lack the ability to develop thermotolerance. This deficiency is explained by the elimination of stress-inducible Hsp70 and Hsp25 response in the absence of Hsf1 activity, leading to a lack of Hsp-mediated inhibition of apoptotic cell death via both caspase-dependent and caspase-independent pathways. The pivotal role of the Hsf1 transactivator in regulating rapid synthesis of Hsps as a critical cellular defense mechanism against environmental stress-induced damage is underlined.

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