Hypoxia-induced cell death and changes in hypoxia-inducible factor-1 activity in PC12 cells upon exposure to nerve growth factor.

Abstract

The transcription factor hypoxia-inducible factor-1 (HIF-1) strongly contributes to the expression of adaptive genes under hypoxic conditions. In addition, HIF-1 has been implicated in the regulation of delayed neuronal cell death. Suspension-grown and adherent PC12 cells treated with NGF were used as an experimental model for studying the relationship between hypoxia-induced cell death and activation of HIF-1. Cell damage was assessed by flow cytometry of double-stained (Annexin V and propidiumiodide) cells, and by analysis of the overall death parameters LDH and mitochondrial dehydrogenase. In parallel, cells were transfected with a control and a three-hypoxia-responsive-elements (HRE)-containing vector and HIF-1-driven luciferase activity was determined. Exposure of NGF-treated PC12 cells to hypoxia resulted in a higher cell death rate when compared to untreated controls. PC12 cells exposed for 2 days to NGF exhibited a decrease of HIF-1 activity up to a factor of ten. This decrease may contribute to the enhanced hypoxia-induced cell death via reduced expression of HIF-1alpha-regulated genes responsible for adaptation to hypoxia, like those for glucose transport proteins and enzymes of the glycolytic chain. The decrease in HIF-1 activity and the increase in hypoxia sensitivity may suggest that NGF act as an hierarchically organized signaling molecule.

• Authors: Nico Charlier, Norbert Leclere, Ursula Felderhoff, Julia Heldt, Thomas Kietzmann, Michael Obladen, Johann Gross
• Journal: Brain research. Molecular brain research (Brain Res Mol Brain Res) Vol. 104 Issue 1 Pg. 21-30 (Jul 15 2002) ISSN: 0169-328X [Print] Netherlands
• PMID: 12117547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Annexin A5
• DNA-Binding Proteins
• HIF1A protein, human
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nuclear Proteins
• Transcription Factors
• Propidium
• Nerve Growth Factor
• Luciferases

Topics

• Animals
• Annexin A5
• Apoptosis (drug effects, physiology)
• Asphyxia Neonatorum (metabolism, physiopathology)
• Cell Death (drug effects, physiology)
• Cell Survival (drug effects, physiology)
• Central Nervous System (metabolism, physiopathology)
• DNA-Binding Proteins (metabolism)
• Dose-Response Relationship, Drug
• Genes, Reporter (drug effects, physiology)
• Genetic Vectors (drug effects, physiology)
• Humans
• Hypoxia, Brain (metabolism, physiopathology)
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Infant, Newborn
• Luciferases (genetics)
• Necrosis
• Nerve Growth Factor (metabolism, pharmacology)
• Neurons (drug effects, metabolism)
• Nuclear Proteins (metabolism)
• PC12 Cells
• Phenotype
• Propidium
• Rats
• Transcription Factors