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Fig. 6. Oxygen-sensing synopsis under (A) normoxia and (B) hypoxia. In normoxia, HIF-{alpha} is constitutively synthesized and sent to proteosomal destruction, controlled by PHD-dependent hydroxylation. In addition, NAD(P)H oxidase as the major donor of ROS has been implicated in controlling HIF-{alpha} stability, potentially involving the iron-mediated Fenton reaction. Reduced O2 levels in hypoxia result in stabilization of HIF-{alpha} and subsequent HIF-target gene expression due to declining O2-dependent PHD and NAD(P)H oxidase activity. Further, during hypoxic events mitochondria have been suggested to be the major source of ROS formation at complex III, aiding HIF-{alpha} stabilization. In addition, as a consequence of the declining mitochondrial membrane potential, an impaired cytosolic calcium buffering dominates, which triggers transmitter release or ion channel conductivity eliciting a hypoxic cellular response. Not all ROS-mediated pathways on HIF activity are part of an oxygen-signaling response but rather expression of a delicate integration of oxygen-sensing mechanisms into major growth factor signaling pathways.





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