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

ABSTRACT: Homeostatic control of oxygen availability allows cells to survive oxygen deprivation. Although the transcription factor hypoxia-inducible factor 1? (HIF-1?) 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 ?-secretase-dependent cleavage to provide a positive feed-forward mechanism required for oxygen-dependent HIF-1? 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-1? degradation. p75(NTR) stabilizes Siah2 by decreasing its auto-ubiquitination. Genetic loss of p75(NTR) dramatically decreases Siah2 abundance, HIF-1? stabilization, and induction of HIF-1? target genes in hypoxia. p75(NTR-/-) mice show reduced HIF-1? 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.

SUBMITTER: Le Moan N 

PROVIDER: S-EPMC3212815 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature