Figure 2: Activation and inactivation pathways for hypoxia-induced factor 1 (HIF-1) in normoxia, hypoxia/anoxia, and cancer. (a) In normoxic normal cells, molecular oxygen (O2) sensing by membrane NADPH oxidase results in formation of superoxide radical anions and subsequently in the control of the HIF-1 signaling pathway via proteolytic degradation of the HIF-1α subunit. These events prevent the recruitment of functional HIF-1 which results from heterodimerization of HIF-1α and β subunits. In anoxia/hypoxia, a severe drop in the levels of NADPH oxidase-driven superoxide radical anion prevents oxidative and proteolytic damage of the HIF-1α subunit which then becomes available to form functional HIF-1 and results in signaling activation. In cancer cells, the HIF-1 signaling pathway may be overexpressed via, for instance, mechanisms illustrated in Panel b. (b) This panel details hydroxylation and the subsequent steps of the HIF-1 inactivation pathway and its disruption in cancer cells. Mechanisms that neutralize the HIF-1 pathway in cancer cells may include alteration of gene expression for succinate dehydrogenase and fumarase (the net results of which are a rise in succinate levels which interfere with the hydroxylation steps by product inhibition) (mechanism 1) and for von Hippel-Lindau protein (mechanism 2) (preventing formation of E3-ubiquitin ligase proteic complex and hence HIF-1α inactivation). Other comments are in the text.