ZFIN ID: ZDB-PUB-191212-39
p53 Protects Cells from Death at the Heatstroke Threshold Temperature
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.
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:
  • Animals
  • Apoptosis*
  • Ataxia Telangiectasia Mutated Proteins/metabolism
  • HCT116 Cells
  • HSC70 Heat-Shock Proteins/metabolism
  • Heat Shock Transcription Factors/metabolism
  • Heat Stroke/genetics
  • Heat Stroke/metabolism*
  • Heat-Shock Response*
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Protein Stability
  • Tumor Suppressor Protein p53/genetics
  • Tumor Suppressor Protein p53/metabolism*
  • Zebrafish
  • bcl-2-Associated X Protein/metabolism
PubMed: 31825845 Full text @ Cell Rep.
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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.
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