| First Author | Le Moan N | Year | 2011 |
| Journal | Mol Cell | Volume | 44 |
| Issue | 3 | Pages | 476-90 |
| PubMed ID | 22055192 | Mgi Jnum | J:180679 |
| Mgi Id | MGI:5306839 | Doi | 10.1016/j.molcel.2011.08.033 |
| Citation | Le Moan N, et al. (2011) Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1alpha. Mol Cell 44(3):476-90 |
| abstractText | Homeostatic control of oxygen availability allows cells to survive oxygen deprivation. Although the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) 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 gamma-secretase-dependent cleavage to provide a positive feed-forward mechanism required for oxygen-dependent HIF-1alpha 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-1alpha degradation. p75(NTR) stabilizes Siah2 by decreasing its auto-ubiquitination. Genetic loss of p75(NTR) dramatically decreases Siah2 abundance, HIF-1alpha stabilization, and induction of HIF-1alpha target genes in hypoxia. p75(NTR-/-) mice show reduced HIF-1alpha 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. |
