p53 Protects Cells from Death at the Heatstroke Threshold Temperature

Area of Science:

• Molecular Biology
• Cellular Stress Response
• Oncology

Background:

• Heatstroke (core body temperature >40°C) is life-threatening.
• The tumor suppressor p53 is known to induce apoptosis at hyperthermia (>41°C).
• The function of p53 at sub-heatstroke temperatures (≤40°C) is not well understood.

Purpose of the Study:

• To investigate the role of p53 at the heatstroke threshold temperature (40°C).
• To elucidate the mechanism by which p53 influences the heat shock response (HSR) at 40°C.
• To explore the therapeutic implications of p53's role in heat stress for cancer treatment.

Main Methods:

• Utilized zebrafish and human cell models.
• Analyzed the activation of heat shock proteins (Hsf1, Hsp90) and p53 at 40°C.
• Investigated the impact of p53 deficiency on tumor xenograft growth under heat treatment.
• Examined the role of ATM kinase in p53 phosphorylation and apoptosis induction.

Main Results:

• p53 promotes survival at 40°C by dampening a hyperreactive heat shock response.
• At 40°C, Hsp90 stabilizes p53, which represses Hsf1 and Hsc70 to maintain homeostasis.
• Hyperthermia (>41°C) activates ATM, leading to p53 phosphorylation at S37, BAX upregulation, and apoptosis.
• 40°C treatment inhibited the growth of p53-deficient tumor xenografts but not p53+/+ tumors.

Conclusions:

• p53 plays a crucial role in cell survival at the heatstroke threshold temperature (40°C) by regulating the HSR.
• The findings reveal a dual role for p53 in heat stress response, promoting survival at 40°C and apoptosis at higher temperatures.
• Targeting p53 status may offer a personalized therapeutic strategy for p53-deficient cancers under heat stress conditions.