Endocrine Abstracts

The interplay between the von Hippel Lindau (VHL) protein and hypoxia-inducible factor (HIF) will be reviewed and the extent to which this explains the pathogenesis of VHL disease will be discussed.
HIF is a master regulator of the transcriptional response to diminished tissue oxygenation, controlling such processes as angiogenesis, erythropoietin production, cellular metabolism and influencing cell proliferation / survival decisions. HIF itself is a heterodimer, dominantly regulated via effects on its alpha chain. Recent studies have indicated that in normoxia HIF alpha chains are targeted for proteasomal destruction as a result of enzymatic hydroxylation of particular prolyl residues, by a group of iron and oxoglutarate dependent dioxygenases. Furthermore, in normoxia asparaginyl hydroxylation, mediated by another oxoglutarate dependent dioxygenase, Factor Inhibiting HIF (FIH), blocks the transcriptional response by blocking co-activator recruitment. VHL protein plays a part in both processes, acting as the recognition component of the ubiquitin ligase involved in normoxic HIF alpha chain destabilisation and interacting with FIH.
The relationship between disease associated mutations in VHL protein and these functions will be discussed as will the contributions of these processes to the development of tissue specific tumours.