Redox regulation of nerve growth factor-induced neuronal differentiation of PC12 cells through modulation of the nerve growth factor receptor, TrkA.
We investigated the effects of the cellular redox state on nerve growth factor (NGF)-induced neuronal differentiation and its signaling pathways. Treatment of PC12 cells with buthionine sulfoximine (BSO) reduced the levels of GSH, a major cellular reductant, and enhanced NGF-induced neuronal differentiation, activation of AP-1 and the NGF receptor tyrosine kinase, TrkA. Conversely, incubation of the cells with a reductant, N-acetyl-L-cysteine (NAC), inhibited NGF-induced neuronal differentiation and AP-1 activation. Consistent with the suppression, NAC inhibited NGF-induced activation of TrkA, formation of receptor complexes comprising TrkA, Shc, Grb2, and Sos, and activation of phospholipase Cgamma and phosphatidylinositol 3-kinase. Biochemical analysis suggested that the cellular redox state regulates TrkA activity through modulation of protein tyrosine phosphatases (PTPs). Thus, cellular redox state regulates signaling pathway of NGF through PTPs, and then modulates neuronal differentiation.
Kamata
Hideaki
H
Department of Life Science, Graduate School of Science, University of Hyogo, Khoto 3-2-1, Kamigori-chou, Ako-gun, Hyogo, 678-1297, Japan. h_kamata@sci.himeji-tech.ac.jp
Oka
Shin-ichi
S
Shibukawa
Yukinao
Y
Kakuta
Jungo
J
Hirata
Hajime
H
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D016716:PC12 Cells; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
D018808:Transcription Factor AP-1; D019328:Buthionine Sulfoximine; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D017027:Protein Tyrosine Phosphatases; D005978:Glutathione; D000111:Acetylcysteine