PUBLICATION

p53 Protects Cells from Death at the Heatstroke Threshold Temperature

Authors
Gong, L., Zhang, Q., Pan, X., Chen, S., Yang, L., Liu, B., Yang, W., Yu, L., Xiao, Z.X., Feng, X.H., Wang, H., Yuan, Z.M., Peng, J., Tan, W.Q., Chen, J.
ID
ZDB-PUB-191212-39
Date
2019
Source
Cell Reports   29: 3693-3707.e5 (Journal)
Registered Authors
Chen, Jun
Keywords
ATM, Hsc70, Hsf1, Hsp90, cell death, heatstroke threshold temperature, human cell, hyperthermia temperature, p53, zebrafish
MeSH Terms
  • HCT116 Cells
  • MCF-7 Cells
  • Apoptosis*
  • Humans
  • Protein Stability
  • bcl-2-Associated X Protein/metabolism
  • Animals
  • Mice, Inbred BALB C
  • HSC70 Heat-Shock Proteins/metabolism
  • Mice, Nude
  • Mice
  • Hep G2 Cells
  • Ataxia Telangiectasia Mutated Proteins/metabolism
  • Zebrafish
  • Tumor Suppressor Protein p53/genetics
  • Tumor Suppressor Protein p53/metabolism*
  • Heat-Shock Response*
  • Heat Stroke/genetics
  • Heat Stroke/metabolism*
  • Heat Shock Transcription Factors/metabolism
(all 20)
PubMed
31825845 Full text @ Cell Rep.
Abstract
When the core body temperature is higher than 40°C, life is threatened due to heatstroke. Tumor repressor p53 is required for heat-induced apoptosis at hyperthermia conditions (>41°C). However, its role in sub-heatstroke conditions (≤40°C) remains unclear. Here, we reveal that both zebrafish and human p53 promote survival at 40°C, the heatstroke threshold temperature, by preventing a hyperreactive heat shock response (HSR). At 40°C, both Hsf1 and Hsp90 are activated. Hsf1 upregulates the expression of Hsc70 to trigger Hsc70-mediated protein degradation, whereas Hsp90 stabilizes p53 to repress the expression of Hsf1 and Hsc70, which prevents excessive HSR to maintain cell homeostasis. Under hyperthermia conditions, ATM is activated to phosphorylate p53 at S37, which increases BAX expression to induce apoptosis. Furthermore, growth of p53-deficient tumor xenografts, but not that of their p53+/+ counterparts, was inhibited by 40°C treatment. Our findings may provide a strategy for individualized therapy for p53-deficient cancers.
Genes / Markers
Figures
No images available
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zdf1
    Point Mutation
    1 - 1 of 1
    Show
    Human Disease / Model
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    hsf1MO1-hsf1MRPHLNO
    hspa8MO1-hspa8MRPHLNO
    tp53MO4-tp53MRPHLNO
    1 - 3 of 3
    Show
    Fish
    Antibodies
    Orthology
    Engineered Foreign Genes
    No data available
    Mapping