Three researchers have won the 2019 Nobel Prize in Physiology or Medicine “for their discoveries of how cells sense and adapt to oxygen availability.”
Dr. Gregg L. Semenza
William G. Kaelin Jr., MD; Sir Peter J. Ratcliffe, MB ChB, MD; and Gregg L. Semenza, MD, PhD, described the molecular machinery that regulates gene activity in response to oxygen levels.
Their work “established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function” and “paved the way for promising new strategies to fight anemia, cancer, and many other diseases,” according to a statement by The Nobel Assembly at Karolinska Institutet.
Dr. Semenza, of Johns Hopkins Medicine in Baltimore, studied how the erythropoietin (EPO) gene is regulated by oxygen levels. Via experiments in mice, he identified DNA segments next to the EPO gene that mediate the response to hypoxia.
Dr. Ratcliffe, of the University of Oxford (England) and the Francis Crick Institute in London, also studied oxygen-dependent regulation of the EPO gene. Both his and Dr. Semenza’s groups found the oxygen-sensing mechanism was present in nearly all tissues.
Dr. Peter Ratcliffe
Dr. Semenza also discovered a protein complex, hypoxia-inducible factor (HIF), that binds to the identified DNA segments in an oxygen-dependent manner. Additional investigation revealed that HIF consists of two transcription factors, HIF-1a and ARNT.
Several research groups found that HIF-1a is protected from degradation in hypoxia. In low-oxygen conditions, the amount of HIF-1a increases so it can bind to and regulate EPO and other genes with HIF-binding DNA segments. However, at normal oxygen levels, ubiquitin is added to HIF-1a, tagging it for degradation in the proteasome. It wasn’t clear how ubiquitin binds to HIF-1a in an oxygen-dependent manner, but Dr. Kaelin’s work provided some insight.
Dr. William G. Kaelin Jr.
Dr. Kaelin, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, was researching von Hippel-Lindau’s (VHL) syndrome, an inherited disorder in which mutations can lead to tumors in multiple organs. He found the VHL gene encodes a protein that prevents cancer onset, and cancer cells without a functional VHL gene express high levels of hypoxia-regulated genes.
Research by other groups showed that VHL is part of a complex that labels proteins with ubiquitin, tagging them for degradation. Dr. Ratcliffe and his group found that VHL is required for the degradation of HIF-1a at normal oxygen levels.
Dr. Kaelin’s and Dr. Ratcliffe’s groups also showed that, under normal oxygen conditions, hydroxyl groups are added at two locations in HIF-1a. This modification – prolyl hydroxylation – allows VHL to bind to HIF-1a. So the researchers found that normal oxygen levels control HIF-1a degradation with the help of prolyl hydroxylases.
Additional research by Dr. Ratcliffe’s group and others revealed the specific prolyl hydroxylases involved in HIF-1a degradation. The researchers also found that HIF-1a’s gene-activating function was regulated by oxygen-dependent hydroxylation.
This work has improved the understanding of how different oxygen levels regulate physiological processes. In particular, oxygen sensing is essential for erythropoiesis, so these findings have implications for the treatment of anemia.
“There are several drugs that are now in clinical trials that serve to increase HIF activity and, as a result, will increase the production of erythropoietin and stimulate red blood cell production,” Dr. Semenza said in an interview after the announcement of his Nobel win. “These are all small molecules that can be given by mouth, and that may be a great convenience for patients who, at the present time, may require injections of recombinant human erythropoietin.”