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

Clin Cancer Res. 2005 Nov 1;11(21):7607-13. doi: 10.1158/1078-0432.CCR-05-0981.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Apoptosis
  • Blotting, Western
  • Catalase / metabolism
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Glucose / metabolism
  • Glutaredoxins
  • Humans
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
  • Imidazoles / pharmacology
  • Ischemia
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Models, Biological
  • Oxidoreductases / metabolism
  • Pancreatic Neoplasms / metabolism*
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Binding
  • Pyridines / pharmacology
  • Reactive Oxygen Species
  • Signal Transduction*
  • Thioredoxins / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Enzyme Inhibitors
  • Glutaredoxins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Imidazoles
  • Pyridines
  • Reactive Oxygen Species
  • Thioredoxins
  • Oxidoreductases
  • Catalase
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Mitogen-Activated Protein Kinase 8
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • VHL protein, human
  • Glucose
  • SB 203580