The eIF4E2-Directed Hypoxic Cap-Dependent Translation Machinery Reveals Novel Therapeutic Potential for Cancer Treatment

Figure 3

Both eIF4E- and eIF4E2-dependent translation initiations are active in the range of human physiological tissue oxygenation. The mean partial pressure of oxygen in human tissues (physioxia) ranges from 29.2 ± 1.8 mmHg in the muscle to 72 ± 20 mmHg in the kidney (or the equivalent of 3.8 ± 0.2% O₂ to 9.5 ± 2.6% O₂). The ability of mTORC1 to phosphorylate and inactivate the eIF4E repressor 4EBP decreases significantly between 1 and 3% O₂. This allows eIF4E-dependent translation to remain active between 1 and 21% O₂. Furthermore, the eIF4E2 hypoxic activator HIF-2α is stabilized below 8% O₂, allowing eIF4E2-dependent translation to be active in the low to midrange of human physioxia. Therefore, there is a window during physiological tissue oxygenation where eIF4E and eIF4E2 are cooperating to produce the cellular proteome. It is important to note that to achieve the indicated oxygen concentrations in cell culture media, 24 h is required for the dissolved oxygen to equilibrate with the ambient air.