• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α.

Homeostatic control of oxygen availability allows cells to survive oxygen deprivation. Although the transcription factor hypoxia-inducible factor 1α (HIF-1α) is the main regulator of the hypoxic response, the upstream mechanisms required for its stabilization remain elusive. Here, we show that p75 neurotrophin receptor (p75(NTR)) undergoes hypoxia-induced γ-secretase-dependent cleavage to provide a positive feed-forward mechanism required for oxygen-dependent HIF-1α stabilization. The intracellular domain of p75(NTR) directly interacts with the evolutionarily conserved zinc finger domains of the E3 RING ubiquitin ligase Siah2 (seven in absentia homolog 2), which regulates HIF-1α degradation. p75(NTR) stabilizes Siah2 by decreasing its auto-ubiquitination. Genetic loss of p75(NTR) dramatically decreases Siah2 abundance, HIF-1α stabilization, and induction of HIF-1α target genes in hypoxia. p75(NTR-/-) mice show reduced HIF-1α stabilization, vascular endothelial growth factor (VEGF) expression, and neoangiogenesis after retinal hypoxia. Thus, hypoxia-induced intramembrane proteolysis of p75(NTR) constitutes an apical oxygen-dependent mechanism to control the magnitude of the hypoxic response.

Pubmed ID: 22055192


  • Le Moan N
  • Houslay DM
  • Christian F
  • Houslay MD
  • Akassoglou K


Molecular cell

Publication Data

November 4, 2011

Associated Grants

  • Agency: NINDS NIH HHS, Id: R01 NS051470
  • Agency: NINDS NIH HHS, Id: R01 NS051470-08
  • Agency: NINDS NIH HHS, Id: R01 NS052189
  • Agency: NINDS NIH HHS, Id: R01 NS052189-09
  • Agency: NINDS NIH HHS, Id: R01NS051470
  • Agency: NINDS NIH HHS, Id: R01NS052189
  • Agency: NCRR NIH HHS, Id: RR18928

Mesh Terms

  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Animals
  • Anoxia
  • Cell Hypoxia
  • Disease Models, Animal
  • HEK293 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Oxygen
  • Proteasome Endopeptidase Complex
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational
  • Protein Stability
  • Receptors, Nerve Growth Factor
  • Retinal Neovascularization
  • Time Factors
  • Transfection
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Vascular Endothelial Growth Factor A