Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease

Steele, Andrew D.; Hütter, Gregor; Jackson, Walker S.; Heppner, Frank L.; Borkowski, Andrew W.; King, Oliver D.; Raymond, Gregory J.; Aguzzi, Adriano; Lindquist, Susan

doi:10.1073/pnas.0806319105

Cited by 64 publications

(56 citation statements)

References 59 publications

(68 reference statements)

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“…While being a prominent longevity factor in nematodes (27,28), the influence of HSF1 on mammalian lifespan has been little explored. In some strains, Hsf1 compromise has no effect on lifespan (5,29). However, we found that in the mixed background used for our NPcis experiments, Hsf1 knockouts had a shorter lifespan than Hsf1 +/+ controls.…”

Section: Figurecontrasting

confidence: 38%

Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis

Dai

Santagata²,

Tang³

et al. 2012

J. Clin. Invest.

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123

151

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Intrinsic stress response pathways are frequently mobilized within tumor cells. The mediators of these adaptive mechanisms and how they contribute to carcinogenesis remain poorly understood. A striking example is heat shock factor 1 (HSF1), master transcriptional regulator of the heat shock response. Surprisingly, we found that loss of the tumor suppressor gene neurofibromatosis type 1 (Nf1) increased HSF1 levels and triggered its activation in mouse embryonic fibroblasts. As a consequence, Nf1 -/-cells acquired tolerance to proteotoxic stress. This activation of HSF1 depended on dysregulated MAPK signaling. HSF1, in turn, supported MAPK signaling. In mice, Hsf1 deficiency impeded NF1-associated carcinogenesis by attenuating oncogenic RAS/MAPK signaling. In cell lines from human malignant peripheral nerve sheath tumors (MPNSTs) driven by NF1 loss, HSF1 was overexpressed and activated, which was required for tumor cell viability. In surgical resections of human MPNSTs, HSF1 was overexpressed, translocated to the nucleus, and phosphorylated. These findings reveal a surprising biological consequence of NF1 deficiency: activation of HSF1 and ensuing addiction to this master regulator of the heat shock response. The loss of NF1 function engages an evolutionarily conserved cellular survival mechanism that ultimately impairs survival of the whole organism by facilitating carcinogenesis. IntroductionEvolutionarily conserved from yeasts to humans, the heat shock transcription factor heat shock factor 1 (HSF1) is activated by a broad range of stressors that extend far beyond heat, including heavy metals, UV radiation, hypoxia, desiccation, and acidosis (1). During activation, HSF1 undergoes phosphorylation and other posttranslational modifications, trimerization, and nuclear translocation. This results in rapid, high-affinity binding of HSF1 to consensus heat shock elements (HSEs) within the promoters of target genes (2). Such binding drives the induction or suppression of hundreds of genes in mammalian cells (3).The adaptive response unleashed by HSF1 activation is critical for maintaining homeostasis of the cell's proteome, mediated in large part by increased expression of classical heat shock proteins such as HSP27, HSP70, and HSP90 (4). However, the effect of HSF1 activation goes far beyond these chaperones. It helps coordinate a range of fundamental cellular processes that are important to the fitness of malignant cells, including cell cycle control, ribosome biogenesis, protein translation, and glucose metabolism (5, 6). As a result, HSF1 both facilitates initial oncogenic transformation and maintains the malignant phenotype of established cancer cell lines driven by a wide range of mutations. In mice and in cell culture, genetic ablation of Hsf1 expression potently impairs tumorigenesis and cellular transformation driven by oncogene activation or tumor suppressor loss (5). The importance of HSF1 in enabling malignancy has been demonstrated by other recent work as well

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Section: Figurecontrasting

confidence: 38%

Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis

Dai

Santagata²,

Tang³

et al. 2012

J. Clin. Invest.

Self Cite

123

151

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“…We performed behavioral testing on PrP KOs and controls neural tissue during prion disease. We have recently implicated heat shock factor 1 as a mediator of protection against prion disease in vivo 12 and other research suggests that inflammation is a major contributor to prion pathogenesis. 13 Beyond these observations, the molecular mechanism(s) of prion-induced neuronal toxicity remain unresolved.…”

Section: Resultsmentioning

confidence: 99%

Context dependent neuroprotective properties of prion protein (PrP)

Steele

Zhou

Jackson

et al. 2009

Prion

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“…This response is regulated mainly at the level of transcription by heat shock transcription factor 1 (HSF1) (13)(14)(15). HSF1 protects cells from exposure to extreme temperatures, by inducing the expression of HSP (16)(17)(18)(19), and from various pathophysiological conditions, such as age-related neurodegenerative diseases (20)(21)(22)(23). Because HSF1 can sense even a mild increase in temperature, it has been suggested to play roles in the regulation of genes for inflammatory cytokines (24).…”

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confidence: 99%

Heat Shock Transcription Factor 1 Inhibits Expression of IL-6 through Activating Transcription Factor 3

Takii

Inouye

Fujimoto

et al. 2009

The Journal of Immunology

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The febrile response is a complex physiological reaction to disease, including a cytokine-mediated increase in body temperature and the activation of inflammatory systems. Fever has beneficial roles in terms of disease prognosis, partly by suppressing the expression of inflammatory cytokines. However, the molecular mechanisms underlining the fever-mediated suppression of inflammatory gene expression have not been clarified. In this study, we showed that heat shock suppresses LPS-induced expression of IL-6, a major pyrogenic cytokine, in mouse embryonic fibroblasts and macrophages. Heat shock transcription factor 1 (HSF1) activated by heat shock induced the expression of activating transcription factor (ATF) 3, a negative regulator of IL-6, and ATF3 was necessary for heat-mediated suppression of IL-6, indicating a fever-mediated feedback loop consisting of HSF1 and ATF3. A comprehensive analysis of inflammatory gene expression revealed that heat pretreatment suppresses LPS-induced expression of most genes (86%), in part (67%) via ATF3. When HSF1-null and ATF3-null mice were injected with LPS, they expressed much higher levels of IL-6 than wild-type mice, resulting in an exaggerated febrile response. These results demonstrate a novel inhibitory pathway for inflammatory cytokines.

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Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease

Cited by 64 publications

References 59 publications

Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis

Loss of tumor suppressor NF1 activates HSF1 to promote carcinogenesis

Context dependent neuroprotective properties of prion protein (PrP)

Heat Shock Transcription Factor 1 Inhibits Expression of IL-6 through Activating Transcription Factor 3

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