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. Fumarate hydratase (FH) is a housekeeping gene, but mutations in this gene allows for fumarate 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 it is chemically similar to succinate. Having a double bond in the centre of the dicarboxylic acid, fumarate is a rigid molecule compared to succinate making it a probable possibility for fumarate to interacts better with PHDs.

The Oncogenic Action of Fumarate References