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) act ivation of the IGF-I receptor rescues SH-SY5Y human neuroblastoma cell s from high glucose-mediated programmed cell death (PCD). In the curre nt study, we further explored the potential points in the cell death c ascade where IGF-I receptor activation may afford neuroprotection. As an initial step, we examined the effects of the PCD stimulus, high glu cose, on stress-activated protein kinases, specifically the two mitoge n-activated protein kinases p38 kinase and c-Jun N-terminal kinase (JN K). High glucose treatment activated the tyrosine phosphorylation of b oth p38 kinase and JNK in a dose- and time-dependent fashion. We next examined the effects of IGF-I on JNF and p38 kinase under normoglycemi c and hyperglycemic conditions. IGF-I activated p38 kinase alone and h ad additive effects on glucose-induced p38 kinase phosphorylation. In contrast, IGF-I inhibited glucose activation of JNK phosphorylation an d JNK activity. IGF-I also inhibited the glucose-induced nuclear trans location of JNK, but did not effect glucose-induced translocation of p 38 kinase. Finally, IGF-I inhibition of JNK phosphorylation was blocke d by the mitogen-activated protein kinase/extracellular signal-regulat ed kinase inhibitor, PD98059, Collectively, these data imply cross-tal k between the mitogen-activated protein kinase pathway and JNK and sug gest that IGF-I activation of mitogen-activated protein kinases interf eres with JNK activation and protects cells from PCD.