Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 476-490 |
| Number of pages | 15 |
| Journal | Molecular Cell |
| Volume | 44 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 3 Nov 2011 |
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Keywords
- Hif1alpha
- p75NTR
- p75 neurotrophin receptor
- E3 RING ubiquitin ligase
- Siah2
- hypoxia
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Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α. / Le Moan, Natacha; Houslay, Daniel; Christian, Frank; Houslay, Miles; Akassoglou, Katerina.
In: Molecular Cell, Vol. 44, No. 3, 03.11.2011, p. 476-490.Research output: Contribution to journal › Article
TY - JOUR
T1 - Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1α
AU - Le Moan, Natacha
AU - Houslay, Daniel
AU - Christian, Frank
AU - Houslay, Miles
AU - Akassoglou, Katerina
N1 - Molecular Cell 2011 Nov 4;44(3):476-90
PY - 2011/11/3
Y1 - 2011/11/3
N2 - 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.
AB - 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.
KW - Hif1alpha
KW - p75NTR
KW - p75 neurotrophin receptor
KW - E3 RING ubiquitin ligase
KW - Siah2
KW - hypoxia
UR - http://www.cell.com/molecular-cell/home
U2 - 10.1016/j.molcel.2011.08.033
DO - 10.1016/j.molcel.2011.08.033
M3 - Article
VL - 44
SP - 476
EP - 490
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 3
ER -