The body possesses multiple mechanisms to sense and adapt to hypoxia, or low oxygen levels. One is the aforementioned carotid body control of respiratory rate. Another fundamental physiological adaptation to hypoxia is release of erythropoietin (EPO), a hormone that stimulates production of red blood cells. Both Semenza's and Ratcliffe's work was instrumental in determining how this process is controlled by oxygen availability.2,3 Semenza demonstrated that DNA segments located near the EPO gene modulate the hypoxia response.4 Both he and Ratcliffe independently demonstrated that while EPO is produced in the kidney, nearly all tissues possess this oxygen-sensing mechanism. Furthering this work, using cultured hepatic cells, Semenza identified a protein complex that binds to this DNA segment in an oxygen-dependent manner.3 Semenza termed this protein complex hypoxia-inducible factor (HIF).
When cellular oxygen levels are low, HIF-1α abundance increases, in turn binding and regulating the EPO gene. Normally rapidly degraded via ubiquitination and subsequent proteasomal degradation, HIF-1α is spared from degradation in conditions of hypoxia. Kaelin discovered the key to how oxygen-dependent ubiquitination of HIF-1α occurs through his investigations into von Hippel-Lindau's (VHL) disease, a disease which greatly increases cancer risk in individuals with VHL mutations. As VHL is part of a complex responsible for ubiquitination, and is capable of physically interacting with HIF-1α, it plays an important role in degradation of HIF-1α under normoxic conditions. Ratcliffe then built on this work by demonstrating that VHL regulates post-translational and oxygen-sensitive degradation of HIF‑1α.5 Both Ratcliffe and Kaelin subsequently demonstrated that oxygen regulates the degradation process by the addition of hydroxyl groups to HIF‑1α.5,6
Taken together, the three recipients of the 2019 Nobel Prize in Physiology or Medicine demonstrated that the changes in gene expression in response to oxygen availability are directly dependent on cellular oxygen levels, thereby allowing for immediate cellular response to perturbations in cellular oxygen levels through the HIF transcription factor. As oxygen sensing is critical in many aspects of physiology, these discoveries led to greater understanding of many physiological and pathological processes, including muscle function during aerobic versus anaerobic exercise, angiogenesis during fetal development, and in development of diseases such as anemia and cancer.
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