1. [Hypoxia induced HIF-1 accumulation and VEGF expression in gastric epithelial mucosa cell: involvement of ERK1/2 and PI3K/Akt].
- Author
-
Liu L, Ning X, Han S, Zhang H, Sun L, Shi Y, Sun S, Guo C, Yin F, Qiao T, Wu K, and Fan D
- Subjects
- Animals, Cell Hypoxia drug effects, Cell Line, Transformed, Epithelial Cells pathology, Gastric Mucosa pathology, Gene Expression Regulation drug effects, Hydrogen Peroxide pharmacology, Hypoxia pathology, MAP Kinase Signaling System drug effects, Mice, Mitogen-Activated Protein Kinase 1 antagonists & inhibitors, Mitogen-Activated Protein Kinase 3 antagonists & inhibitors, Oxidants pharmacology, Phosphoinositide-3 Kinase Inhibitors, Protein Biosynthesis drug effects, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Ribosomal Protein S6 Kinases, 70-kDa antagonists & inhibitors, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Transcription, Genetic drug effects, Epithelial Cells metabolism, Gastric Mucosa metabolism, Hypoxia metabolism, Hypoxia-Inducible Factor 1, alpha Subunit biosynthesis, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Vascular Endothelial Growth Factor A biosynthesis
- Abstract
Hypoxia is a common environmental stress that influences signaling pathways and cells function, which through initiating intracellular signaling pathways and hence leading to the activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). In this study, we initially confirm that hypoxia activates HIF-1alpha protein expression in a time-dependent manner with a maximum reached at 60 min in vitro and 4h in vivo in gastric mucosa epithelial cells. The expression of HIF-1alpha is correlated with the activation of HIF-1 DNA binding and transcriptional activity. Hypoxia dose not affect HIF-1alpha mRNA transcription but regulates HIF-1alpha protein expression through a translation-dependent pathway to regulate protein synthesis. Hypoxia could induce phosphorylation of Akt, MAPK (ERK), and target of p70S6K1. PI3K and MAPK inhibitor, LY294002 and U0126 could inhibit hypoxia-induced HIF-1 and VEGF expression. We also investigated the role of reactive oxygen species (ROS) involved in HIF-1 and VEGF expression Exogenous addition of H2O2 was sufficient to activate Akt and ERK, scavengers of H2O2 significantly inhibited hypoxia-induced Akt and ERK, and subsequent HIF-lax expression and transcriptional activity. In conclusion, our data suggested that hypoxia- PI3K signaling through Akt and ERK kinases regulated ROS-dependent, hypoxia- induced HIF-1 activation and VEGF expression in gastric mucosa epithelial cells.
- Published
- 2008