Oxidative Stress-induced Phospholipase C-γ1 Activation Enhances Cell Survival
Autor: | Karen McCullough, Graham Carpenter, Xiantao Wang, Xue-Jie Wang, Nikki J. Holbrook |
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Rok vydání: | 2001 |
Předmět: |
Time Factors
Cell Survival MAP Kinase Kinase 4 Immunoblotting Biology Biochemistry Cell Line Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Growth factor receptor Animals Enzyme Inhibitors Phosphorylation Molecular Biology Alleles Protein Kinase C Protein kinase C Mitogen-Activated Protein Kinase Kinases Cell Death Dose-Response Relationship Drug Phospholipase C Phospholipase C gamma JNK Mitogen-Activated Protein Kinases Cell Differentiation Inositol trisphosphate Tyrosine phosphorylation Hydrogen Peroxide Cell Biology Fibroblasts Precipitin Tests Cell biology Enzyme Activation Isoenzymes Oxidative Stress chemistry Type C Phospholipases embryonic structures Second messenger system Tyrosine Signal transduction Cell Division Signal Transduction |
Zdroj: | Journal of Biological Chemistry. 276:28364-28371 |
ISSN: | 0021-9258 |
DOI: | 10.1074/jbc.m102693200 |
Popis: | Phospholipase C-gamma1 (PLC-gamma1) is rapidly activated in response to growth factor stimulation and plays an important role in regulating cell proliferation and differentiation through the generation of the second messengers diacylglycerol and inositol 1,4,5-trisphosphate, leading to the activation of protein kinase C (PKC) and increased levels of intracellular calcium, respectively. Given the existing overlap between signaling pathways that are activated in response to oxidant injury and those involved in responding to proliferative stimuli, we investigated the role of PLC-gamma1 during the cellular response to oxidative stress. Treatment of normal mouse embryonic fibroblasts (MEF) with H2O2 resulted in time- and concentration-dependent tyrosine phosphorylation of PLC-gamma1. Phosphorylation could be blocked by pharmacological inhibitors of Src family tyrosine kinases or the epidermal growth factor receptor tyrosine kinase, but not by inhibitors of the platelet-derived growth factor receptor or phosphatidylinositol 3-kinase. To investigate the physiologic relevance of H2O2-induced tyrosine phosphorylation of PLC-gamma1, we compared survival of normal MEF and PLC-gamma1-deficient MEF following exposure to H2O2. Treatment of PLC-gamma1-deficient MEF with H2O2 resulted in rapid cell death, whereas normal MEF were resistant to the stress. Pretreatment of normal MEF with a selective pharmacological inhibitor of PLC-gamma1, or inhibitors of inositol trisphosphate receptors and PKC, increased their sensitivity to H2O2, whereas treatment of PLC-gamma1-deficient MEF with agents capable of directly activating PKC and enhancing calcium mobilization significantly improved their survival. Finally, reconstitution of PLC-gamma1 protein expression in PLC-gamma1-deficient MEF restored cell survival following H2O2 treatment. These findings suggest an important protective function for PLC-gamma1 activation during the cellular response to oxidative stress. |
Databáze: | OpenAIRE |
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