Low temperature protects mammalian cells from apoptosis initiated by various stimuli in vitro.
Mild hypothermia shows protective effects on patients with brain damage and cardiac arrest. To elucidate the molecular mechanisms underlying these effects, we examined the effects of low temperature (32 degrees C) on cells exposed to a variety of stress in vitro. We found that 32 degrees C suppressed induction of apoptosis by cytotoxic stimuli such as adriamycin, etoposide, thapsigargin, NaCl, H(2)O(2), and anti-Fas antibody. In adriamycin-treated BALB/3T3 cells, the down-shift in temperature from 37 degrees C to 32 degrees C increased the Bcl-xL protein level and decreased the mRNA level of Puma and mitochondrial translocation of Bax, suppressing caspase-9-mediated apoptosis. Furthermore, the protein level and stability of p53 were decreased, and its nuclear export was increased concomitant with Mdm2 mRNA upregulation. The low temperature effect was not observed in p53(-/-)/Mdm2(-/-) mouse embryonic fibroblasts, suggesting that the effect is mediated by suppression of the p53 pathway. In contrast, while thapsigargin-induced apoptosis was suppressed by the low temperature, no effect on the p53 protein level was observed. Furthermore, the survival rate of p53(-/-)/Mdm2(-/-) cells exposed to thapsigargin was increased when cultured at 32 degrees C compared with 37 degrees C. In conclusion, mild hypothermia protects cells from a variety of stress by p53-dependent and p53-independent mechanisms.
Sakurai
Toshiharu
T
Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.
Itoh
Katsuhiko
K
Liu
Yu
Y
Higashitsuji
Hiroaki
H
Sumitomo
Yasuhiko
Y
Sakamaki
Kazuhiro
K
Fujita
Jun
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D041702:BALB 3T3 Cells; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007036:Hypothermia, Induced; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013696:Temperature; D019284:Thapsigargin / Q000494:pharmacology; D019014:fas Receptor
D020536:Enzyme Activators; C491901:FAS protein, human; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D019284:Thapsigargin; D004317:Doxorubicin