Stress protein flux during recovery from simulated ischemia: induced heat shock protein 70 confers cytoprotection by suppressing JNK activation and inhibiting apoptotic cell death.
Multiple stress proteins are recruited in response to stress in living cells. There are limited reports in the literature analyzing multiple stress protein shifts and their functional consequences on stress response. Using two-dimensional electrophoresis we have analyzed shifts in stress protein profiles in response to energy deprivation as a model of ischemic injury to kidneys. A group of chaperones and stress-induced mitogen activated protein (MAP) kinases were analyzed. In addition to examining stress protein induction and phosphorylation we have also examined the mechanism of cytoprotection by heat shock protein 70 (Hsp70). Our results show that, of the different stress proteins examined, only binding protein (BiP) and Hsp70 were significantly induced upon energy deprivation. Other stress proteins, including Hsp27, calnexin, Hsp90 and ERp57 showed alterations in their phosphorylation profiles. Three different MAP kinases, namely p38, extracellular signal regulated kisase and c-jun N-terminal kinase (JNK) were activated in response to energy deprivation. While JNK activation was linked to apoptosis, activated-p38 was involved in phosphorylation of Hsp27. Study of inhibitors of Hsp70 induction or pre-induction of Hsp70 indicated that induced Hsp70 was involved in the suppression of JNK activation thereby inhibiting apoptotic cell death. Our results provide important insights into the flux in stress protein profiles in response to simulated ischemia and highlight the antiapoptotic, cytoprotective mechanism of Hsp70 action.
Kumar
Yadunanda
Y
Department of Biochemistry, Indian Institute of Science, Bangalore, India.
Tatu
Utpal
U
D000255:Adenosine Triphosphate / Q000378:metabolism; D000968:Antimycin A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D004734:Energy Metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation
D018840:HSP70 Heat-Shock Proteins; D009363:Neoplasm Proteins; D000968:Antimycin A; D000255:Adenosine Triphosphate; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases