Bidirectional regulation of p38 kinase and c-Jun N-terminal protein kinase by insulin-like growth factor-I.
We have previously shown that insulin-like growth factor I (IGF-I) activation of the IGF-I receptor rescues SH-SY5Y human neuroblastoma cells from high glucose-mediated programmed cell death (PCD). In the current study, we further explored the potential points in the cell death cascade where IGF-I receptor activation may afford neuroprotection. As an initial step, we examined the effects of the PCD stimulus, high glucose, on stress-activated protein kinases, specifically the two mitogen-activated protein kinases p38 kinase and c-Jun N-terminal kinase (JNK). High glucose treatment activated the tyrosine phosphorylation of both p38 kinase and JNK in a dose- and time-dependent fashion. We next examined the effects of IGF-I on JNK and p38 kinase under normoglycemic and hyperglycemic conditions. IGF-I activated p38 kinase alone and had additive effects on glucose-induced p38 kinase phosphorylation. In contrast, IGF-I inhibited glucose activation of JNK phosphorylation and JNK activity. IGF-I also inhibited the glucose-induced nuclear translocation of JNK, but did not effect glucose-induced translocation of p38 kinase. Finally, IGF-I inhibition of JNK phosphorylation was blocked by the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, PD98059. Collectively, these data imply cross-talk between the mitogen-activated protein kinase pathway and JNK and suggest that IGF-I activation of mitogen-activated protein kinases interferes with JNK activation and protects cells from PCD.
Cheng
H L
HL
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Feldman
E L
EL
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D014407:Tumor Cells, Cultured; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D000730:Androstadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D019000:Phosphotyrosine; D007334:Insulin-Like Growth Factor I; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin