We have spend much time studying how the body deals with and utilizes the toxic byproducts of dioxygen reduction. What happens when the body doesn't get enough dioxygen - a condition call anoxia (no dioxygen) or hypoxia (too little dioxygen)? This might occur in muscles undergoing vigorous exercise, and in the brain and heart when clots occlude blood flow to these organs (as occurs in most strokes and heart attacks). Under low dioxygen concentrations, a family of protein transcription factors called hypoxia-inducible factor (HIF) become activated. The functional proteins appears to be a dimer of HIF-α and HIF-β. In contrast to the concentration of the beta form, the activity of HIF-α is increased under low dioxygen concentrations. HIF-α concentration is regulated not at the transcriptional level, but through proteolysis of the protein. In the presence of abundant dioxygen, HIF-α is hydroxylated at two Pro residues by the enzyme prolyl hydroxlase. This post-translational modification targets the protein for proteolysis (through ubiquitination by the VHL protein and subsequent cleavage by the proteasome). A second independent pathway in rapidly growing tissue leads to increased expression of HIF-α even in the presence of dioxygen. This could be beneficial to cells since rapidly growing tissue, especially tumor cells, might be expected to experience low oxygen conditions.
Figure: Cell response to hypoxia