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

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	heat exposure	Prim-5 to Long-pec	whole organism decreased life span, abnormal	Fig. 1
WT	heat exposure	Prim-15	whole organism hsp70.3 expression increased amount, abnormal	Fig. S2
WT	heat exposure	Prim-15	whole organism hspa4l expression increased amount, abnormal	Fig. S2
WT	heat exposure	Prim-15	whole organism hspa8 expression increased amount, abnormal	Fig. S2
WT	heat exposure	Prim-15	whole organism hspb1 expression increased amount, abnormal	Fig. S2
WT	heat exposure	Prim-15	whole organism hspb8 expression increased amount, abnormal	Fig. S2
WT	heat exposure	Prim-15	whole organism hspd1 expression increased amount, abnormal	Fig. S2
WT	heat exposure	Prim-15	whole organism hsph1 expression increased amount, abnormal	Fig. S2
WT	heat exposure	Prim-15	whole organism tp53 expression increased amount, abnormal	Fig. 1
WT	heat exposure	Prim-5 to Long-pec	whole organism dead, abnormal	Fig. 1

1 - 10 of 29

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
zdf1		Point Mutation	tp53

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
hsf1	MO1-hsf1	MRPHLNO
hspa8	MO1-hspa8	MRPHLNO
tp53	MO4-tp53	MRPHLNO

Fish

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Gong et al., 2019 ZDB-PUB-191212-39 PMID:31825845

p53 Protects Cells from Death at the Heatstroke Threshold Temperature

Gong et al., 2019

ZDB-PUB-191212-39
PMID:31825845