Nerve Growth Factor Treatment Prevents the Increase in Superoxide Produced by Epidermal Growth Factor in PC12 Cells

Stimulation of pheochromocytoma (PC12) cells with the mitogen epidermal growth factor (EGF) produced a rapid and robust accumulation of intracellular reactive oxygen species (ROS), an accumulation which, in other systems, has been shown to be essential for mitogenesis. Brief pretreatment of the cell...

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Bibliographic Details
Published in:The Journal of biological chemistry 1998-08, Vol.273 (35), p.22165-22168
Main Authors: Mills, Edward M., Takeda, Kazuyo, Yu, Zu-Xi, Ferrans, Victor, Katagiri, Yasuhiro, Jiang, Hao, Lavigne, Mark C., Leto, Thomas L., Guroff, Gordon
Format: Article
Language:English
Subjects:
Animals
Epidermal Growth Factor - pharmacology
ErbB Receptors - drug effects
Nerve Growth Factors - pharmacology
PC12 Cells
Rats
Reactive Oxygen Species
Signal Transduction - drug effects
Superoxides - metabolism
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Summary:Stimulation of pheochromocytoma (PC12) cells with the mitogen epidermal growth factor (EGF) produced a rapid and robust accumulation of intracellular reactive oxygen species (ROS), an accumulation which, in other systems, has been shown to be essential for mitogenesis. Brief pretreatment of the cells with nerve growth factor (NGF) suppressed the EGF-mediated ROS increase. EGF failed to produce elevations in ROS in a PC12 variant stably expressing a dominant-negative p21ras construct (PC12-N17) or in cells pretreated with the MEK inhibitor PD098059. NGF failed to suppress the increase in ROS in the PC12 variant nnr5, which lacks p140trk receptors. The suppression of the increase in ROS by NGF was restored in nnr5 cells stably expressing p140trk (nnr5-trk), but NGF failed to prevent the increase in ROS in nnr cells expressing mutant p140trk receptors that lack binding sites for Shc and phospholipase Cγ. Among several inhibitors of superoxide-generating enzymes, only the lipoxygenase inhibitor, nordihydroguaiaretic acid reduced EGF-mediated ROS accumulation. The inhibitory action of NGF on ROS production was mimicked by the nitric oxide donor, sodium nitroprusside, and was blocked by an inhibitor of nitric-oxide synthetase, l-nitroarginine methyl ester. These results suggest a novel mechanism for the rapid interruption of mitogenic signaling by the neurotrophin NGF.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.273.35.22165