Negative regulation of hypoxia inducible factor-1alpha by necdin

FEBS Lett. 2005 Jul 4;579(17):3797-801. doi: 10.1016/j.febslet.2005.05.072.

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that mediates cellular and systemic homeostatic responses to reduce O2 availability, such as erythropoiesis, angiogenesis, and glycolysis. Using the yeast two-hybrid screening system, we found that the oxygen dependent degradation (ODD) domain of HIF-1alpha interacts with necdin, a growth suppressor. The interaction of necdin with HIF-1alpha was confirmed using coimmunoprecipitation with the overexpressed HIF-1alpha. Biological effect of necdin on HIF-1alpha showed that necdin reduces the transcriptional activity of HIF-1 under hypoxia. Moreover, necdin decreased the level of the HIF-1alpha protein, but not that of mRNA, implying a possibility of necdin-mediated HIF-1alpha degradation. Furthermore, necdin has an anti-angiogenic activity in the tube formation assay and CAM assay, which might be due to the downregulation of HIF-1alpha. Collectively, these results suggest that necdin can be a novel negative regulator of HIF-1alpha stability via the direct interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / genetics
  • Angiogenesis Inhibitors / metabolism*
  • Down-Regulation*
  • Endothelium, Vascular / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oxygen / metabolism
  • Protein Structure, Tertiary
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation*
  • Transfection
  • Two-Hybrid System Techniques

Substances

  • Angiogenesis Inhibitors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Transcription Factors
  • necdin
  • Oxygen