Hypoxia-inducible factor In many tumours, oxygen availability becomes limited (hypoxia) very quickly during cancer development. The major regulator of the response to hypoxia is the HIF transcription factor. Under normal oxygen levels, the protein levels of HIF alpa is very low due to constant degradation, mediated by a sequence of post-translational modification events catalyzed by the enzymes PHD1,2 and 3, (also known as EglN2,1 and 3). Under hypoxic conditions, HIF alpha escapes hydroxylation and degration. Succinate dehydrogenase (SDH) is a collection of housekeeping genes (SDHA,B,C,D), but mutations in those genes allows for succinate to accumulate and cross the mitochondrial barrier through a dicarboxylate carrier. Once in the cytosol, it inhibits the activity of the PHD1,2 and 3 since succinate is a product of the enzyme, it acts as feedback inhibition.

The Oncogenic Action of Succinate References