SUPPRESSION OF NERVE GROWTH FACTOR-INDUCED NEURONAL DIFFERENTIATION OF PC12 CELLS - N-ACETYLCYSTEINE UNCOUPLES THE SIGNAL-TRANSDUCTION FROMRAS TO THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE

The cellular redox state is thought to play an important role in a wid e variety cellular signaling pathways. Here, we investigated the invol vement of redox regulation in the nerve growth factor (NGF) signaling pathway and neuronal differentiation in PC12 cells. N acetyl-L-cystein e (NAG), which acts as a reductant in cells both by its direct reducin g activity and by increasing the synthesis of the cellular antioxidant glutathione, inhibited neuronal differentiation induced by NGF or by the expression of oncogenic ras in PC12 cells. NAC suppressed NGF-indu ced c-fos gene expression and AP-1 activation. These results suggest t hat neuronal differentiation and NGF signaling are subject to regulati on by the cellular redox state. NAC also suppressed the NGF-induced ac tivation of mitogen-activated protein kinases (MAPKs) and decreased th e amount of tyrosine phosphorylation of MAPKs. The suppression of MAPK by NAC was independent of glutathione synthesis. In parallel with the suppression of MAPK, the activation of MAPK kinase kinase activity wa s also suppressed in the presence of NAG. In contrast, NGF-induced act ivation of has was not inhibited by NAG. The inhibitory effect of NAC on the MAPK cascade was independent of transcription and translation. Thus, NAC suppresses NGF-induced neuronal differentiation by uncouplin g the signal transduction from Ras to the MAP kinase cascade in PC12 c ells.