10 months ago

Just now, oxygen sensing work won the 2019 Physiology Nobel Prize.

At 5:30 pm on October 7th, Beijing time, the 2019 Nobel Prize in Physiology or Medicine was announced. There were three winners. They were William Kelly from the Dana-Farber Cancer Institute of Harvard Medical School. Kaelin, Jr.), Peter J. Ratcliffe of the University of Oxford and the Francis Crick Institute, and Gregg L of the Johns Hopkins University School of Medicine . Semenza).

Reasons for winning: recognition of their contribution to understanding the mechanisms of cell perception and adaptation to oxygen changes.

The signal recognition system in which the organism feels the oxygen concentration is the most basic function of life, but the academic community knows little about it. Three scientists have elucidated the basic principles of human and most animal cells' oxygen levels at the molecular level, revealing important signaling mechanisms that open up new diseases for anemia, cardiovascular disease, macular degeneration, and cancer. Clinical treatment approach.

Oxygen is the electron acceptor of many biochemical metabolic pathways. The scientific research on oxygen induction and oxygen homeostasis begins with erythropoietin (EPO). When oxygen is deficient, the kidneys secrete EPO to stimulate the bone marrow to produce new red blood cells. For example, when we are active at high altitudes, due to lack of oxygen, the body's metabolism changes, and new blood vessels begin to grow, creating new red blood cells. What these scientists do is to find out the gene expression behind this body reaction. They found that the "switch" of this reaction is a protein called Hypoxia-inducible factors (HIF), but its function is much more than just a switch.

In the early 1990s, Semenza and Ratcliffe began to study how hypoxia caused EPO production. They found a transcriptional enhancer HIF that not only changes with changes in oxygen concentration, but also controls the expression level of EPO. If a DNA fragment is inserted next to a gene, it is induced by hypoxia. . In 1995, Semenza and postdoctoral Wang Guang purified HIF-1 and found that it contains two proteins: HIF-1α and HIF-1β, and confirmed that HIF-1 mediates the body under hypoxic conditions through red blood cells and angiogenesis. Adaptive response.

Subsequently, Semenza and Ratcliffe expanded the types of genes induced by hypoxia. They found that in addition to EPO, HIF-1 binds to and activates a variety of other genes involved in processes such as metabolic regulation, angiogenesis, embryonic development, immunity, and tumors in mammalian cells.

In addition, they observed a dramatic decrease in the number of HIF-1 when cells were converted to hyperoxia, which was only able to activate the target gene when hypoxic. So what is the reason for pushing HIF-1 damage? The answer comes from an unexpected direction.

Von Hippel–Lindau disease (VHL syndrome) is a rare autosomal dominant hereditary disease. VHL patients are characterized by multiple tumors due to the loss of VHL protein, involving many important organs such as brain, bone marrow, retina, kidney, adrenal gland, etc. Typical tumors are composed of inappropriate new blood vessels. Oncologist William Kaelin has been trying to figure out its pathology. However, just in the second year of HIF purification, Kaelin found that VHL protein can negatively regulate HIF-1 via oxygen-dependent proteolysis. Subsequent studies by Kaelin and Ratcliffe found that dioxygenase plays an important role in the recognition of HIF-1 by VHL proteins.

HIF controls the complex and precise response of the human body and most animal cells to oxygen changes, and the three scientists step by step reveal the mysteries of the Earth's life. Research directions to achieve therapeutic goals through the regulation of the HIF pathway are playing a huge role, and their work is and will continue to benefit humanity.


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