oxidants and antioxidants in biology - Oxygen Club of California

Nitric oxide (NO) mimics hypoxia by accumulating HIF-1
BERNHARD BRÜNE AND JIE ZHOU
Dept. of Cell Biology, University of Kaiserslautern, Germany
Hypoxia inducible factor-1 (HIF-1) is a heterodimer composed
of stability regulated HIF-1α and constitutively expressed HIF-1β.
HIF-1 binds to HRE (hypoxia response elements) and enhances
transcription of hypoxia-inducible genes to orchestrate cellular adaptation
to decreased oxygen availability.
Recent evidence suggests that HIF-1α is subjected to stability
regulation under normoxia by NO, either liberated by chemically
distinct NO donors or generated by iNOS. NO signaling is cGMPindependent
but demanded an active phosphotidylinositol-3-
kinase/AKT pathway. Mechanistically, we propose that NO interferes
with HIF-1α degradation by decreasing its ubiquitination
which results from an attenuated pVHL (von Hippel-Lindau protein,
a putative E3-ubiquitin ligase)-HIF-1α interaction. This is
consistent with an impaired prolyl hydroxylase (HIF-PH) activity
which functions as a putative oxygen sensor. As expected, NOeffects
are subjected to modulation by superoxide formation with
the further notion that the effects of NO is dramatically different
under hypoxia, when NO suppressed rather than provoked HIF-1α
accumulation.
Our studies imply stabilization of HIF-1α in close association
with the formation of NO under normoxic conditions. Thus, HIF-1
apart from regulating the cell response to hypoxia may help to coordinate
a proper cell response to inflammation, i.e., NO formation.
Correspondence: bruene@rhrk.uni-kl.de
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