HIF-1 (hypoxia-inducible factor-1) has been shown to essentially control the cellular response to hypoxia. Hypoxia stabilizes the inducible alpha-subunit, preventing post-translational hydroxylation and subsequent degradation via the proteasome. In recent years, clear evidence has emerged that HIF-1alpha is also responsive to many stimuli under normoxic conditions, including thrombin, growth factors, vasoactive peptides, insulin, lipopolysaccharide and cytokines such as TNF-alpha (tumour necrosis factor-alpha), and in many cases reactive oxygen species are involved. One important mechanism underlying these responses is the transcriptional regulation of HIF-1alpha by the redox-sensitive transcription factor NF-kappaB (nuclear factor kappaB), which binds at a distinct element in the proximal promoter of the HIF-1alpha gene. More recently, NF-kappaB binding to this site in the HIF-1alpha promoter has been shown also under hypoxic conditions. Thus these two major pathways regulating the responses to inflammation and oxidative stress on the one hand, and hypoxia on the other hand, appear to be intimately linked. In this issue of the Biochemical Journal, a study by van Uden et al. has supported these findings further, in which they have confirmed the binding of several proteins of the NF-kappaB family at the previously identified consensus site in the HIF-1alpha promoter and shown that TNF-alpha can also transcriptionally induce HIF-1alpha by this previously described pathway. The identification of HIF-1alpha as a target gene of NF-kappaB will have important implications for a variety of disorders related to hypoxia-ischaemia and/or inflammation and oxidative stress.     «

HIF-1 (hypoxia-inducible factor-1) has been shown to essentially control the cellular response to hypoxia. Hypoxia stabilizes the inducible alpha-subunit, preventing post-translational hydroxylation and subsequent degradation via the proteasome. In recent years, clear evidence has emerged that HIF-1alpha is also responsive to many stimuli under normoxic conditions, including thrombin, growth factors, vasoactive peptides, insulin, lipopolysaccharide and cytokines such as TNF-alpha (tumour necrosi...     »