title: 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.
abstract: OBJECTIVE
  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)).
  
  
  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.
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, PA 15213, USA.
authors.forename: Seok J
authors.initials: SJ
authors.lastname: Kwon
authors.forename: Jae J
authors.initials: JJ
authors.lastname: Song
authors.forename: Yong J
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D015153:Blotting, Western; D002374:Catalase / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D054477:Glutaredoxins; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007093:Imidazoles / Q000494:pharmacology; D007511:Ischemia; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D008954:Models, Biological; D010088:Oxidoreductases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013879:Thioredoxins / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D054477:Glutaredoxins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D013879:Thioredoxins; D010088:Oxidoreductases; D002374:Catalase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C497446:VHL protein, human; D005947:Glucose; C093642:SB 203580