How protein kinase C activation protects nerve cells from oxidative stress-induced cell death.

Abstract

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 PKCdelta. Inhibition of either ERK or JNK activation blocks TPA-mediated protection, whereas p38 MAPK and PKCdelta 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.

• Authors: P Maher
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 21 Issue 9 Pg. 2929-38 (May 01 2001) ISSN: 1529-2401 [Electronic] United States
• PMID: 11312276 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Flavonoids
• Isoenzymes
• Reactive Oxygen Species
• Homocysteine
• homocysteic acid
• Glutamic Acid
• Buthionine Sulfoximine
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Protein Kinase C
• Calcium-Calmodulin-Dependent Protein Kinases
• Mitogen-Activated Protein Kinases
• Tetradecanoylphorbol Acetate
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Buthionine Sulfoximine (pharmacology)
• Calcium-Calmodulin-Dependent Protein Kinases (antagonists & inhibitors)
• Cell Count
• Cell Death (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• Glutamic Acid (toxicity)
• Homocysteine (analogs & derivatives, pharmacology)
• Isoenzymes (antagonists & inhibitors, metabolism)
• Mice
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Neurons (cytology, drug effects, metabolism)
• Oxidative Stress (drug effects, physiology)
• Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Tetradecanoylphorbol Acetate (pharmacology)