OPPOSING EFFECTS OF ERK AND JNK-P38 MAP KINASES ON APOPTOSIS

Apoptosis plays an important role during neuronal development, and def ects in apoptosis may underlie various neurodegenerative disorders, To characterize molecular mechanisms that regulate neuronal apoptosis, t he contributions to cell death of mitogen-activated protein (MAP) kina se family members, including ERK (extracellular signal-regulated kinas e), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined af ter withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromoc ytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs, The effects of dominant-interferi ng or constitutively activated forms of various components of the JNK- p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of ap optosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be impo rtant in determining whether a cell survives or undergoes apoptosis.