The Nobel Prize in Medicine for 2019 was awarded to Gregg L. Semenza, William G. Kaelin, and Sir Peter J. Ratcliffe, for discovering the molecular mechanisms that enable cells to sense and adapt to changes in the body’s oxygen levels. A press release listing the reasons for awarding the prize stated that the decoding of this mechanism was based, to a large extent, upon a discovery by the 2004 winners of the Nobel Prize in chemistry, Professors Aaron Ciechanover, Avram Hershko—members of the Israel Academy of Sciences and Humanities—and Professor Irwin Rose.
One of the mechanisms for sensing the level of oxygen in the body and coping with a shortage of it is based on erythropoietin (EPO), a hormone that increases the production of red blood cells, which carry oxygen to the body’s tissues. Although this mechanism was known to the researchers, it was not clear how it was activated by a shortage of oxygen. Professor Semenza and, later on, Professor Ratcliffe identified the region in the gene encoded for the hormone and what caused the level of oxygen to regulate it, and found that this region was shared by many genes whose levels were regulated by oxygen and were expressed in all tissues of the body. At the same time, Professor Semenza isolated a protein known as Hypoxia Inducible Factor (HIF) and showed that when oxygen was in short supply, the levels of HIF in cells increased, activating a series of processes that caused the cell to adapt to the low level of oxygen. Later on, it was found that this protein was made up of two proteins known as HIF-1a and ARNT. Additional studies by Semenza, Ratcliffe, and others showed that these proteins, acting together, were a transcription factor responsible for controlling many genes that produced proteins that helped the cell to adapt to changing oxygen levels.
When the level of oxygen available to cells is low (a state known as hypoxia), the level of HIF-1a increases. When the oxygen level is normal (normoxia), the oxygen oxidizes amino acids that are present on the protein. This chemical change in HIF-1a “attracts” the ubiquitin-proteasome system, which attaches a small peptide known as ubiquitin to the cell, labeling it for disassembly by the proteasome. The level of HIF-1a decreases, stopping the cell’s response to the low oxygen level. The link between ubiquitin and HIF-1a, then, is dependent upon the level of oxygen; when the oxygen level in the cell decreases it stops degrading the HIF-1a protein, and the level of HIF-1a increases, causing the accelerated production of many proteins, including EPO, which speed up the production of red blood cells in order to cope with the lack of oxygen.
Professors Aaron Ciechanover, Avram Hershko, and Irwin Rose were awarded the Nobel Prize in Chemistry in 2004 for their discovery of the ubiquitin-proteasome system.
At the same time, Professor Kaelin’s research on cancerous tumors, particularly in the kidneys, showed that the vast majority of them contained a mutation that paralyzed the activity of a protein known as the von Hippel-Lindau protein (pVHL). The tumors that he studied were found to contain a high level of HIF-1a and, interestingly, were also rich in blood vessels (a response to the lack of oxygen that does not necessarily take place unless the cells sense the lack due to an increase in the level of HIF-1a). Repairing the mutation in the tumor models led to the disappearance of HIF-1a, as well as to the shrinking of the tumors and the blood cells that nourished them. Further studies showed that pVHL was actually a component in the ubiquitin-proteasome system known as an E3 ubiquitin ligase, whose role is to fasten ubiquitin remnants to HIF-1a that has been chemically altered by oxygen before it is destroyed and removed by the proteasome.
The decoding of this complex process plays a significant role in understanding and dealing with various diseases that are linked to oxygen levels in the body or the process of adapting to changes in oxygen levels, such as anemia, cancer, and lung diseases.
A quote from the reasons for awarding the Nobel Prize and from the press release follows:
“Several research groups showed that HIF-1a, which is normally rapidly degraded, is protected from degradation in hypoxia. At normal oxygen levels, a cellular machine called the proteasome, recognized by the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose, degrades HIF-1a. Under such conditions a small peptide, ubiquitin, is added to the HIF-1a protein. Ubiquitin functions as a tag for proteins destined for degradation in the proteasome. How ubiquitin binds to HIF-1a in an oxygen-dependent manner remained a central question.”