[Hypoxia induced HIF-1 accumulation and VEGF expression in gastric epithelial mucosa cell: involvement of ERK1/2 and PI3K/Akt].
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.
Liu
L
L
Ning
X
X
Han
S
S
Zhang
H
H
Sun
L
L
Shi
Y
Y
Sun
S
S
Guo
C
C
Yin
F
F
Qiao
T
T
Wu
K
K
Fan
D
D
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D002461:Cell Line, Transformed; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D006861:Hydrogen Peroxide; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016877:Oxidants; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D042461:Vascular Endothelial Growth Factor A; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse