Prosurvival and prodeath effects of hypoxia-inducible factor-1alpha stabilization in a murine hippocampal cell line

J Biol Chem. 2005 Feb 4;280(5):3996-4003. doi: 10.1074/jbc.M409223200. Epub 2004 Nov 22.


Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator involved in adaptation to hypoxic stress. Previous studies from our laboratory demonstrated that pharmacological activators of HIF-1 (e.g. deferoxamine, cobalt chloride) could also protect cultured primary neurons or an immortalized hippocampal neuroblast line (HT22) from oxidative stress-induced death. However, whether HIF-1 activation is sufficient to abrogate neuronal death resulting from oxidative stress or other hypoxia-independent death inducers remains unclear. To address this question we utilized a HIF-1alpha fusion protein that partially lacks the domain required for oxygen-dependent degradation of HIF-1alpha and that has a VP16 transcriptional activation domain from herpes simplex virus. HT22 cells were infected with a retrovirus encoding either the HIF-1alpha-VP16 fusion protein or the activation domain of the VP16 protein alone as a control. Expression of HIF-1alpha-VP16, but not VP16 alone, increased luciferase activity driven by a canonical hypoxia response element, increased mRNA of established HIF-1 target genes, and increased activity of one of these HIF-1 target genes. Unexpectedly, enhanced HIF-1 activity in HT22 cells enhanced sensitivity to oxidative death induced by glutathione depletion. Accordingly, suppression of HIF-1alpha expression using RNA interference prevented oxidative death. By contrast, HIF-1alpha-VP16-expressing HT22 cells were more resistant to DNA damage (induced by camptothecin) or endoplasmic reticulum stress (induced by thapsigargin and tunicamycin) than were VP16-expressing cells, and suppression of HIF-1alpha expression using RNA interference rendered HT22 cells more sensitive to death induced by DNA damage or endoplasmic reticulum stress. Together, these data demonstrate that HIF-1 can mediate prodeath or prosurvival responses in the same cell type depending on the injury stimulus.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Camptothecin / pharmacology
  • Cell Death / drug effects
  • Cell Death / physiology*
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • DNA Damage
  • Enzyme Inhibitors / pharmacology
  • Herpes Simplex Virus Protein Vmw65 / genetics
  • Hippocampus / cytology*
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mice
  • Neurons / cytology*
  • Neurons / metabolism*
  • Oxygen / pharmacology
  • RNA, Small Interfering
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Thapsigargin / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tunicamycin / pharmacology


  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Herpes Simplex Virus Protein Vmw65
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Tunicamycin
  • Thapsigargin
  • Oxygen
  • Camptothecin