Abstract
Purpose and experimental design:
Previously, we observed that the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH(2)-terminal kinase (JNK1) is mediated through the activation of apoptosis signal-regulating kinase 1 (ASK1) as a result of the reactive oxygen species-mediated dissociation of glutaredoxin and thioredoxin from ASK1. In this study, we examined whether p38 MAPK and JNK1 are involved in the accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) during ischemia. Human pancreatic cancer MiaPaCa-2 cells were exposed to low glucose (0.1 mmol/L) with hypoxia (0.1% O(2)).
Results and conclusions:
During ischemia, p38 MAPK and JNK1 were activated in MiaPaCa-2 pancreatic cancer cells. The activated p38 MAPK, but not JNK1, phosphorylated HIF-1alpha. Data from in vivo binding assay of von Hippel-Lindau tumor suppressor protein with HIF-1alpha suggests that the p38-mediated phosphorylation of HIF-1alpha contributed to the inhibition of HIF-1alpha and von Hippel-Lindau tumor suppressor protein interaction during ischemia. SB203580, a specific inhibitor of p38 MAPK, inhibited HIF-1alpha accumulation during ischemia, probably resulting from the ubiquitination and degradation of HIF-1alpha.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviridae / genetics
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Apoptosis
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Blotting, Western
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Catalase / metabolism
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Electrophoresis, Polyacrylamide Gel
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Glucose / metabolism
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Glutaredoxins
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Humans
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Hypoxia / metabolism
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Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
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Imidazoles / pharmacology
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Ischemia
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MAP Kinase Kinase Kinase 5 / metabolism
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Mitogen-Activated Protein Kinase 8 / metabolism
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Models, Biological
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Oxidoreductases / metabolism
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Pancreatic Neoplasms / metabolism*
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Phosphorylation
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Plasmids / metabolism
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Protein Binding
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Pyridines / pharmacology
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Reactive Oxygen Species
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Signal Transduction*
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Thioredoxins / metabolism
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Enzyme Inhibitors
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Glutaredoxins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Imidazoles
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Pyridines
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Reactive Oxygen Species
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Thioredoxins
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Oxidoreductases
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Catalase
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Von Hippel-Lindau Tumor Suppressor Protein
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Mitogen-Activated Protein Kinase 8
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 5
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VHL protein, human
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Glucose
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SB 203580