MOLECULAR ASPECTS OF OXYGEN SENSING IN PHYSIOLOGICAL ADAPTATION TO HYPOXIA

Oxygen is an essential substrate in aerobic metabolism for most eukary otic organisms. Thus organisms and cells have developed numerous immed iate and long-term compensatory mechanisms for dealing with oxygen dep rivation. Adaptation to hypoxia at the organismal level includes refle x hyperventilation, polycythemia and angiogenesis, which lead to incre ased O-2 delivery to the tissues. Adaptation at the cellular level inv olves a shift from oxidative phosphorylation to anaerobic glycolysis, increased glucose metabolism, and expression of hypoxic stress-related proteins. Regulation of many proteins participating in adaptation to hypoxia occurs at the level of gene expression. The most widespread mo lecular mechanism of hypoxia-dependent regulation is transcriptional i nduction via the binding of a transcription factor, hypoxia-inducible factor-1 (Hif-1), to the specific sequences on the regulated genes. Lo ng-term induction of many proteins also requires an increase in mRNA s tability, which is mediated by the binding of regulatory proteins to s pecific sequences within the mRNAs. The current theories of coupling b etween the O-2 sensor and mechanisms controlling gene expression are d iscussed. (C) 1997 Elsevier Science B.V.