p53 Protects Cells from Death at the Heatstroke Threshold Temperature

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. [Display omitted] •p53 promotes survival by preventing a hyperreactive heat shock response (HSR) at 40°C•Excessive HSC70-mediated protein degradation (hyperreactive HSR) causes death at 40°C•HSP90 stabilizes p53 without phosphorylation at S37 to repress HSR at 40°C•ATM phosphorylates p53 at S37 to induce apoptosis in hyperthermia conditions Gong et al. report that in contrast to promoting apoptosis in hyperthermia conditions, both zebrafish and human tumor repressor p53 protect cells from death by preventing a hyperreactive heat shock response at 40°C, the heatstroke threshold temperature (HTT). They may provide a strategy for individualized therapy for p53-deficient cancers.