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The Journal of Neuroscience, May 1, 2001, 21(9):2929-2938
How Protein Kinase C Activation Protects Nerve Cells from
Oxidative Stress-Induced Cell Death
Pamela
Maher
Department of Cell Biology, The Scripps Research Institute, La
Jolla, California 92037
Oxidative stress is implicated in the nerve cell death that occurs
in a variety of neurological disorders, and the loss of protein kinase
C (PKC) activity has been coupled to the severity of the damage. The
functional relationship between stress, PKC, and cell death is,
however, unknown. Using an immortalized hippocampal cell line that is
particularly sensitive to oxidative stress, I show that activation of
PKC by the phorbol ester tetradecanoylphorbol acetate (TPA) inhibits
cell death via the stimulation of a complex protein phosphorylation
pathway. TPA treatment leads to the rapid activation of extracellular
signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), the
inactivation of p38 mitogen-activated protein kinase (MAPK), and the
downregulation of PKC . Inhibition of either ERK or JNK activation
blocks TPA-mediated protection, whereas p38 MAPK and PKC inhibitors
block stress-induced nerve cell death. Both p38 MAPK inactivation and
JNK activation appear to be downstream of ERK because an agent that
blocks ERK activation also blocks the modulation of these other MAP
kinase family members by TPA treatment. Thus, the protection from
oxidative stress afforded nerve cells by PKC activity requires the
combined modulation of multiple enzyme pathways and suggests why the
loss of PKC activity contributes to nerve cell death.
Key words:
oxidative stress; programmed cell death; MAP kinases; protein kinase C; oxidative glutamate toxicity; reactive oxygen
species
Copyright © 2001 Society for Neuroscience 0270-6474/01/2192929-10$05.00/0
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