Endocrine Abstracts (2003) 6 S10

HIF and cancer

PJ Ratcliffe

University of Oxford, The Wellcome Trust Centre for Human Genetics, Oxford, UK.

Hypoxia inducible factor (HIF) is an a/b heterodimeric transcriptional complex that mediates a broad range of cellular and systemic responses to hypoxia. Transcriptional targets include genes involved in angiogenesis, erythropoiesis, catecholamine metabolism, matrix metabolism, energy metabolism and cell survival decisions. Whilst HIF-b subunits are constitutive nuclear proteins, both the abundance and activity of HIF-a subunits are strongly inducible by hypoxia, leading to formation of an active complex that bindings hypoxia response elements in regulatory DNA sequences. Analysis of HIF-a subunits has demonstrated that activity is regulated by a novel mode of post-translational modification involving a series of oxygen dependent enzymatic hydroxylations at specific prolyl and asparaginyl residues. HIF prolyl hydroxylation is performed by a closely related set of isoenzymes (PHD1-3) that differ in abundance and sub-cellular localization. Hydroxylation of either HIF-1a Pro402 or Pro564 promotes interaction with the von Hippel-Lindau tumour suppressor protein (pVHL). In oxygenated cells this process targets HIF-a for rapid proteasomal destruction. HIF asparaginyl hydroxylation is performed by a protein termed FIH (Factor Inhibiting HIF). In oxygenated cells hydroxylation of HIF-1a Asn 803 prevents interaction with the p300 transcriptional co-activator providing a second mechanism by which HIF mediated transcription is inactivated. In cancer, the system is activated by a variety of genetic and environmental mechanisms, most strikingly by stabilization of HIF-a following inactivation of pVHL in VHL associated tumours. At least in part, HIF activation in cancer accounts for classical tumour associated properties of dysregulated glycolysis and angiogenesis. The role of the HIF system in tumour biology and the potential for therapeutic manipulation will be discussed.

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