how do cells adapt to the absence of oxygen?

This year, three people are rewarded with the Nobel prize of Medicine or Physiology. These are William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza for " their discoveries about how cells perceive and adapt to oxygen availability ". They unveiled the molecular mechanisms regulating the activity genetic, in response to variations in oxygen level. Their work thus explains a process of essential adaptation of the cells, and gives new possibilities to fight theanemia, the cancers, and other diseases that involve cellular perception of theoxygen.

Who are the Nobel Prize winners of Medicine 2019?

William G. Kaelin Jr. is a professor of medicine at Harvard University, specializing in oncology. In 2016, he received the Lasker Award for his research, a prize awarded to people making major advances in medicine. He works in particular on protein tumor suppressors.

Sir Peter J. Ratcliffe is a doctor as well as a cellular and molecular biologist at John Radcliffe Hospital, Oxford University. His Nobel Prize rewards his work on cellular reactions tohypoxiathat is to say, the absence of a sufficient supply of oxygen in a part or the whole body.

Gregg L. Semenza was already known for his discovery of HIF-1, a factor in transcription which allows cancer cells to adapt to environments with low oxygen. He is a professor of genetic medicine, chemistry biological, medicine, pediatrics, and also radiation oncology and molecular radiation.

Why are they rewarded? The beginning of an investigation

The Nobel Prize in Medicine is awarded to them for their explanation of the molecular mechanism governing the cellular response to the variations of oxygen, and more precisely to the absence of oxygen.

A key answer tohypoxia is the increase in levels of erythropoietin (COOL), a hormone mainly produced by kidneys. It stimulates the proliferation of stem cells precursors of erythrocytes, or "red blood cells", more commonly referred to as " Red cells ". Thus, increased levels of EPO lead to increased production of erythrocytes. Semenza was working on how oxygen levels regulate the uncomfortable EPO, just like Ratcliffe. They both independently found that the mechanism of oxygen perception was present in all tissues, not just in the kidneys where EPO is produced. It would be induced by a segment ofDNA located next to the EPO gene.

Subsequently, Semenza identified a protein complex that binds to this DNA segment in an oxygen-dependent manner: the Hypoxia-inducible factor (HIF). In 1995, he discovered the Genoa encoding HIF, which is composed of two protein sub-complexes: HIF-1α and ARNT. Thus, when the oxygen levels are high, the cells contain little HIF-1α. Whereas if oxygen levels are low, the amounts of HIF-1α increase to regulate the EPO on the rise. A mechanism for regulating HIF-1α is degradation by proteasome, a complex enzyme. In order for the proteasome to recognize what it needs to degrade, a small peptic is attached to proteins: theubiquitin. But how can ubiquitin cling to HIF-1α in an oxygen-dependent way?

Crucial discovery and Nobel Prize in Medicine approaches

In his research on Von Hippel-Lindau disease (VHL disease), Kaelin was able to show that cancer cells have abnormally high levels of genes regulated by the disease.hypoxia, if they do not have a functional VHL gene. When the functional gene is reintroduced into the celllevels return to normal. Thanks to others teams of researchersit has been known that the VHL protein is part of a complex that labels other proteins with ubiquitin, causing them to be degraded. These findings allowed Ratcliffe to demonstrate that VHL interacts with HIF-1α and is necessary for HIF-1α to degrade when oxygen levels are normal.

A mystery remained unresolved: how does the oxygen level regulate the interaction between VHL and HIF-1α? In 2001, Kaelin and Ratcliffe published two articles simultaneously highlighting that under normal oxygen levels, hydroxyl groups are added at two specific positions of HIF-1α. This allows VHL to recognize HIF-1α and to grip it, to bring about its degradation by the proteasome. However, the addition of the hydroxyl groups is carried out by prolyl hydroxylases, which are enzymes… sensitive to oxygen! Ratcliffe was also able to identify the prolyl hydroxylases responsible. It was also put in light that the genetic activation function of HIF-1α is regulated by an oxygen-dependent hydroxylation. Treasure hunt done! The chest held three Nobel Prizes of Medicine or Physiology.