The Signaling Nature of Cellular Metabolism: The Hypoxia Signaling

Identification of the hypoxia-inducible factors (HIFs) as core players of the transcriptional response to hypoxia transformed our understanding of the mechanism underpinning the hypoxic response at the molecular level and led to discoveries on the role of metabolism in cell signaling alike. It has now become clear that HIFs act in the heart of a pathway where oxygen may be considered as a signaling entity recognized by molecular sensors conveying the oxygen signal to the transcriptional regulator HIFs as distal effectors. The pathway is under multiple levels of regulatory control shaping the cellular response to hypoxia and gives hypoxia signaling an intricate and dynamic activity profile. These include regulatory mechanisms within the HIF pathway as well as diverse interplay with other metabolic and signaling pathways of critical cellular functions. The emerging model reflects a multi-level regulatory network that apparently affects all aspects of cell physiology.