Signalling hypoxia by protein hydroxylation: Transcriptional architecture of the HIF response

Abstract

Animal use a set of 2‐oxoglutarate dependent dioxygenases to signal cellular oxygen levels to the transcription factor, HIF, via the post‐translational hydroxylation of specific prolyl and asparaginyl residues. These hydroxylations promote the inactivation and proteolytic destruction of HIF and hence regulate a broad range of cellular and systemic responses to hypoxia. The involvement of this system in a many medically important physiological responses presents both an opportunity and challenge, particularly in defining how the system operates to generate co‐ordinated physiological responses, and in understanding how it might be manipulated therapeutically in specific medical conditions. Advances in the understanding of the pan‐genomic architecture of the HIF transcriptional response, will be described together with the implications of activating such extensive pathways in cancer, and mechanisms that modulate the oncogenic output of HIF pathway activation.