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
-
- Heat Shock Transcription Factors/metabolism
- Heat-Shock Response*
- Apoptosis*
- Heat Stroke/genetics
- Heat Stroke/metabolism*
- Zebrafish
- Humans
- Protein Stability
- bcl-2-Associated X Protein/metabolism
- Mice
- HSC70 Heat-Shock Proteins/metabolism
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism*
- MCF-7 Cells
- Mice, Nude
- Animals
- Mice, Inbred BALB C
- HCT116 Cells
- Hep G2 Cells
- Ataxia Telangiectasia Mutated Proteins/metabolism
- PubMed
- 31825845 Full text @ Cell Rep.
Citation
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. (2019) p53 Protects Cells from Death at the Heatstroke Threshold Temperature. Cell Reports. 29:3693-3707.e5.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping