The role of heat-shock proteins in thermotolerance

Parsell, Dawn A.; Taulien, J; Lindquist, Susan

doi:10.1098/rstb.1993.0026

Cited by 167 publications

(26 citation statements)

References 20 publications

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“…During unstressed conditions, constitutively expressed stress proteins may function as molecular chaperones to facilitate the synthesis, folding, or translocation of nascent polypeptides and the translocation or repair of existing polypeptides (9 -11). Similar chaperone functions have been proposed, but not established, for inducible HSPs during cellular adaptation such as thermotolerance (12,13).…”

Section: Heat Shock Transcription Factors (Hsfs)mentioning

confidence: 97%

Targeted Disruption of Heat Shock Transcription Factor 1 Abolishes Thermotolerance and Protection against Heat-inducible Apoptosis

McMillan

Xiao

Shao

et al. 1998

Journal of Biological Chemistry

481

438

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Heat shock transcription factor 1 (HSF1) is a member of the vertebrate HSF family that regulates stress-inducible synthesis of heat shock proteins (HSPs). Although the synthesis of the constitutively expressed and inducible members of the heat shock family of stress proteins correlates with increased cellular protection, their relative contributions in acquired cellular resistance or "thermotolerance" in mammalian cells is presently unknown. We report here that constitutive expression of multiple HSPs in cultured embryonic cells was unaffected by disruption of the murine HSF1 gene. In contrast, thermotolerance was not attainable in hsf1 (؊/؊) cells, and this response was required for protection against heat-induced apoptosis. We conclude that 1) constitutive and inducibly expressed HSPs exhibit distinct physiological functions for cellular maintenance and adaptation, respectively, and 2) other mammalian HSFs or distinct evolutionarily conserved stress response pathways do not compensate for HSF1 in the physiological response to heat shock. Heat shock transcription factors (HSFs)1 regulate stressinducible synthesis of HSPs during development, growth, and adaptation (1-3). This response protects the ischemic heart (4 -6) and promotes tumor cell survival (7,8), thus indicating the clinical importance of this regulatory pathway. During unstressed conditions, constitutively expressed stress proteins may function as molecular chaperones to facilitate the synthesis, folding, or translocation of nascent polypeptides and the translocation or repair of existing polypeptides (9 -11). Similar chaperone functions have been proposed, but not established, for inducible HSPs during cellular adaptation such as thermotolerance (12, 13).Up-regulation of stress protein expression, within minutes after exposure to noxious stimuli, is accomplished through mechanisms that involve both transcriptional activation and preferential translation (2,14). Physiological stresses induce monomers of metazoan HSFs to: 1) oligomerize into trimers that bind DNA with high affinity, 2) translocate into the nucleus, and 3) activate transcription of target stress protein genes (reviewed in Ref.3). HSF1 is the major stress-inducible transactivator of the heat shock response (15); in contrast, HSF2 has been proposed to regulate "nonstress" HSP gene expression during early development stages and spermatogenesis (16 -19).To date, genetic studies indicate pleiotropic functions of the single copy HSF gene in Saccharomyces cerevisiae and Drosophila. Yeast HSF expression is essential for cell viability during unstressed conditions (20 -22), a property that may be related to regulation of basal HSP gene expression (23). Interestingly, the Drosophila HSF protein is not essential for general growth or viability, but is required for larvae development, oogenesis, and survival at extreme stress conditions (24). In vertebrates, multiple HSFs have been identified in chicks, plants, mice, and humans (16,(25)(26)(27). We hypothesize that members of the mammalian HSF fa...

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Section: Heat Shock Transcription Factors (Hsfs)mentioning

confidence: 97%

Targeted Disruption of Heat Shock Transcription Factor 1 Abolishes Thermotolerance and Protection against Heat-inducible Apoptosis

McMillan

Xiao

Shao

et al. 1998

Journal of Biological Chemistry

481

438

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“…15 and E.V., unpublished results), but they appear to be dispensable for this function in yeast and other bacteria (16,17). Although other Hsps may also contribute to thermotolerance, in general they appear to be important for growth at higher temperatures rather than necessary for the specific adaptation processes involved in acquired thermotolerance (18).…”

mentioning

confidence: 99%

Mutants of Arabidopsis thaliana defective in the acquisition of tolerance to high temperature stress

Hong

Vierling

2000

Proc. Natl. Acad. Sci. U.S.A.

386

334

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The ability of organisms to acquire thermotolerance to normally lethal high temperatures is an ancient and conserved adaptive response. However, knowledge of cellular factors essential to this response is limited. Acquisition of thermotolerance is likely to be of particular importance to plants that experience daily temperature fluctuations and are unable to escape to more favorable environments. We developed a screen, based on hypocotyl elongation, for mutants of Arabidopsis thaliana that are unable to acquire thermotolerance to high-temperature stress and have defined four separate genetic loci, hot1-4, required for this process. hot1 was found to have a mutation in the heat shock protein 101 (Hsp101) gene, converting a conserved Glu residue in the second ATP-binding domain to a Lys residue, a mutation that is predicted to compromise Hsp101 ATPase activity. In addition to exhibiting a thermotolerance defect as assayed by hypocotyl elongation, 10-day-old hot1 seedlings were also unable to acquire thermotolerance, and hot1 seeds had greatly reduced basal thermotolerance. Complementation of hot1 plants by transformation with wild-type Hsp101 genomic DNA restored hot1 plants to the wild-type phenotype. The hot mutants are the first mutants defective in thermotolerance that have been isolated in a higher eukaryote, and hot1 represents the first mutation in an Hsp in any higher plant. The phenotype of hot1 also provides direct evidence that Hsp101, which is required for thermotolerance in bacteria and yeast, is also essential for thermotolerance in a complex eukaryote.

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“…A key feature of this response includes the transcriptional up-regulation of several heat shock proteins that are known to confer protection against a subsequent exposure to an otherwise lethal cellular stressor, including ␥-radiation, hyperthermia, and chemotherapeutic agents (1,2). By comparison, an initial exposure of cells to a more severe or prolonged bout of hyperthermia is known to overcome this protective heat shock response and induce apoptosis or necrosis (3).…”

mentioning

confidence: 99%

Activation of Caspase-9, but Not Caspase-2 or Caspase-8, Is Essential for Heat-induced Apoptosis in Jurkat Cells

Shelton

Dillard

Robertson

2010

Journal of Biological Chemistry

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Exposure of cells to hyperthermia is known to induce apoptosis, although the underlying mechanisms are only partially understood. Here, we examine the molecular requirements necessary for heat-induced apoptosis using genetically modified Jurkat T-lymphocytes. Cells stably overexpressing Bcl-2/ Bcl-x L or stably depleted of Apaf-1 were completely resistant to heat-induced apoptosis, implicating the involvement of the mitochondria-mediated pathway. Pretreatment of wild-type cells with the cell-permeable biotinylated general caspase inhibitor b-VAD-fmk (biotin-Val-Ala-Asp(OMe)-CH 2 F) both inhibited heat-induced apoptosis and affinity-labeled activated initiator caspase-2, -8, and -9. Despite this finding, however, cells engineered to be deficient in caspase-8, caspase-2, or the caspase-2 adaptor protein RAIDD (receptor-interacting protein (RIP)-associated Ich-1/CED homologous protein with death domain) remained susceptible to heat-induced apoptosis. Additionally, b-VAD-fmk failed to label any activated initiator caspase in Apaf-1-deficient cells exposed to hyperthermia. Cells lacking Apaf-1 or the pro-apoptotic BH3-only protein Bid exhibited lower levels of heat-induced Bak activation, cytochrome c release, and loss of mitochondrial membrane potential, although cleavage of Bid to truncated Bid (tBid) occurred downstream of caspase-9 activation. Combined, the data suggest that caspase-9 is the critical initiator caspase activated during heat-induced apoptosis and that tBid may function to promote cytochrome c release during this process as part of a feed-forward amplification loop.Sublethal heat exposure is known to induce an evolutionarily conserved adaptive response known as the heat shock response. A key feature of this response includes the transcriptional up-regulation of several heat shock proteins that are known to confer protection against a subsequent exposure to an otherwise lethal cellular stressor, including ␥-radiation, hyperthermia, and chemotherapeutic agents (1, 2). By comparison, an initial exposure of cells to a more severe or prolonged bout of hyperthermia is known to overcome this protective heat shock response and induce apoptosis or necrosis (3). Significantly, because hyperthermia can induce apoptosis, it is currently being tested in combination with conventional anti-cancer therapy in clinical trials for advanced malignancies (4, 5). Additionally, there is a growing interest in developing ways to more selectively target tumor cells with hyperthermia for therapeutic use (6, 7).There are two distinct apoptotic pathways: (i) the mitochondria-mediated (i.e. intrinsic) pathway and (ii) the receptor-mediated (i.e. extrinsic) pathway. The extrinsic pathway is activated upon binding of a death ligand to its cognate receptor (e.g. Fas binding to the Fas receptor), which causes the receptors to move within close proximity to one another and recruit the adaptor protein Fas-associated protein with death domain (FADD), followed by the recruitment of initiator procaspase-8 or -10 (8, 9). This protein comp...

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The role of heat-shock proteins in thermotolerance

Cited by 167 publications

References 20 publications

Targeted Disruption of Heat Shock Transcription Factor 1 Abolishes Thermotolerance and Protection against Heat-inducible Apoptosis

Targeted Disruption of Heat Shock Transcription Factor 1 Abolishes Thermotolerance and Protection against Heat-inducible Apoptosis

Mutants of Arabidopsis thaliana defective in the acquisition of tolerance to high temperature stress

Activation of Caspase-9, but Not Caspase-2 or Caspase-8, Is Essential for Heat-induced Apoptosis in Jurkat Cells

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