Heavy! [Oxygen Perception Path] won the 2019 Nobel Prize in Physiology or Medicine

Today, the 2019 Nobel Prize in Physiology or Medicine was announced, and Professor William G. Kaelin, Professor Peter J. Ratcliffe, and Professor Gregg L. Semenza won the award. The Nobel Prize review pointed out that the three scientists discovered a vital oxygen-sensing pathway for humans and the survival of most animals.

▲ Professor William G. Kaelin (left), Professor Peter J. Ratcliffe (middle), and Professor Gregg L. Semenza (right) (Source: Reference [1])

Find regulatory genes

It is well known that most animals, including humans, cannot be separated from oxygen. But our demand for oxygen must reach a delicate balance. In the absence of oxygen, we will suffocate and die; if there is too much oxygen, we will be poisoned again. To this end, the creature has evolved many sophisticated mechanisms to control the balance of oxygen. For example, for cells buried deep in the tissue, red blood cells can send them oxygen. Once the oxygen content is too low, the body will promote the formation of red blood cells, keeping the concentration of oxygen within a reasonable range.

In the 1990s, Professor Ratcliffe and Professor Semenza wanted to understand the mechanism behind this phenomenon. They found that a particular DNA sequence appeared to be involved in gene activation caused by hypoxia. If this DNA sequence is inserted near other genes, these genes can also be induced to activate in a hypoxic environment. In other words, this DNA sequence actually plays a regulatory role in a low oxygen environment. Subsequent studies have also shown that once this sequence is mutated, the organism is at a loss for a hypoxic environment.

Subsequent studies have found that this sequence regulates a protein called HIF-1 in the cell, which is a combination of HIF-1α and HIF-1β. In an anoxic environment, HIF-1 is capable of binding and activating specific genes in many mammalian cells. Interestingly, none of these genes are responsible for the production of erythropoietin. These results suggest that there is a more complex cause behind erythropoiesis caused by hypoxia. In the subsequent regulatory pathways, HIF-1 plays a central role in regulating many key genes including VEGF, which promotes angiogenesis.

Degradation of HIF-1 protein

As a key regulatory protein, HIF-1 initiates gene expression in anoxic environment. In an oxygen-rich environment, this protein is degraded. What kind of mechanism is behind this? No one thought that the answer was hidden in a seemingly completely unrelated direction.

Let us turn the topic to Professor William G. Kaelin. At the time, the scientist was studying a cancer syndrome called VHL disease. He found that in a typical VHL tumor, there are often abnormally formed new blood vessels. In addition, he also found more VEGF and erythropoietin. So he naturally thinks whether the hypoxic pathway has a role in this disease.

In 1996, analysis of patient cells showed that some genes that should have disappeared in an oxygen-rich environment were unexpectedly expressed in large numbers. Adding a normal function of VHL protein can reverse this phenomenon. Further research indicates that the specific ability of VHL proteins is derived from specific proteins that bind to them, including certain ubiquitin ligases. Under the action of this enzyme, proteins that are not required by the cells are labeled as "discarded" and sent to the proteasome for degradation.

▲ Ubiquitin degradation pathway (Source: Rogerdodd [GFDL ( http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 ( http://creativecommons.org/licenses/by -sa/3.0/)], via Wikimedia Commons)

Interestingly, it was immediately discovered that in the oxygen-rich environment, the component of HIF-1, HIF-1α, was degraded by this route. In 1999, the team of Professor Ratcliffe discovered that the degradation of HIF-1α requires VHL protein involvement. Professor Kaelin also proved that VHL and HIF-1α will directly bind. Later, many researchers gradually reduced the whole process - in the oxygen-rich environment, VHL will bind HIF-1α and guide the ubiquitination degradation of the latter.

Exquisite regulation

Why is HIF-1α only degraded in an oxygen-rich environment? The researchers further analyzed the binding region of HIF-1α and VHL and found that if a proline was removed, its ubiquitination was inhibited. This is the key to the regulation of HIF-1α! In an oxygen-rich environment, an oxygen atom combines with a hydrogen atom of valine to form a hydroxyl group. This step requires the participation of prolyl hydroxylase.

Since this step requires the participation of oxygen atoms, it is easy to understand why HIF-1α is not degraded in anoxic environments.

▲ Schematic diagram of the path of oxygen sensing by organisms (Source: Reference [2], Credit: Cassio Lynm)

Revealing the biological oxygen sensing pathway not only has its value in basic science, but also hopes to bring innovative therapies. For example, if the HIF-1 pathway can be regulated and the production of red blood cells is promoted, it is expected to treat anemia. Interfering with the degradation of HIF-1 can promote angiogenesis and treat poor circulation.

On the other hand, because tumors are inseparable from neovascularization, if we can degrade HIF-1α or related proteins (such as HIF-2α), we are expected to fight malignant tumors. Currently, similar therapies have entered the early stages of clinical trials.

In summary, the findings of these three scientists have important value in basic research and clinical applications. The subtle revealing of the biologically-aware oxygen pathway highlights the wisdom of human beings in challenging the unknown. We congratulate the three scientists again. Being able to win the Nobel Prize in Physiology or Medicine is the best recognition of their achievements! (Pharmaceutical Kanto)