Signal pathway of hypoxia-inducible factor-1alpha phosphorylation and its interaction with von Hippel-Lindau tumor suppressor protein during ischemia in MiaPaCa-2 pancreatic cancer cells.
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.
Mesh Terms:
Adenoviridae, Anoxia, Apoptosis, Blotting, Western, Catalase, Cell Line, Tumor, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Enzyme Activation, Enzyme Inhibitors, Glucose, Glutaredoxins, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Imidazoles, Ischemia, MAP Kinase Kinase Kinase 5, Mitogen-Activated Protein Kinase 8, Models, Biological, Oxidoreductases, Pancreatic Neoplasms, Phosphorylation, Plasmids, Protein Binding, Pyridines, Reactive Oxygen Species, Signal Transduction, Thioredoxins, Von Hippel-Lindau Tumor Suppressor Protein, p38 Mitogen-Activated Protein Kinases
Adenoviridae, Anoxia, Apoptosis, Blotting, Western, Catalase, Cell Line, Tumor, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Enzyme Activation, Enzyme Inhibitors, Glucose, Glutaredoxins, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Imidazoles, Ischemia, MAP Kinase Kinase Kinase 5, Mitogen-Activated Protein Kinase 8, Models, Biological, Oxidoreductases, Pancreatic Neoplasms, Phosphorylation, Plasmids, Protein Binding, Pyridines, Reactive Oxygen Species, Signal Transduction, Thioredoxins, Von Hippel-Lindau Tumor Suppressor Protein, p38 Mitogen-Activated Protein Kinases
Clin. Cancer Res.
Date: Nov. 01, 2005
PubMed ID: 16278378
View in: Pubmed Google Scholar
Download Curated Data For This Publication
103784
Switch View:
- Interactions 1