The Janus-faced effects of hypoxia on astrocyte function.

Astrocytes are increasingly recognized for their impact on neuronal function and viability in health and disease. Hypoxia has Janus-faced influences on astrocytes and their ability to support neuronal viability. For example, hypoxia induces astrocyte-dependent protection of neurons following hypoxia preconditioning.

The good, the bad, and the cell type-specific roles of hypoxia inducible factor-1 alpha in neurons and astrocytes.

Hypoxia inducible factor-1alpha (HIF-1alpha) is a key regulator of oxygen homeostasis, because it is responsible for the regulation of genes involved in glycolysis, erythropoiesis, angiogenesis, and apoptosis. In the CNS, HIF-1alpha is stabilized by insults associated with hypoxia and ischemia. Because its many target genes mediate both adaptive and pathological processes, the role of HIF-1alpha in neuronal survival is debated.

In cultured astrocytes, p53 and MDM2 do not alter hypoxia-inducible factor-1alpha function regardless of the presence of DNA damage.

A principal molecular mechanism by which cells respond to hypoxia is by activation of the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha). Several studies describe a binding of p53 to HIF-1alpha in a protein complex, leading to attenuated function, half-life, and abundance of HIF-1alpha. However, these reports almost exclusively utilized transformed cell lines, and many employed transfection of p53 or HIF-1alpha plasmid constructs and/or p53 and HIF-1alpha reporter constructs as surrogates for endogenous protein activity and target expression, respectively.