What is Alpha Oxygen

How cells can live with a lack of oxygen

Stockholm. This year's Nobel Prize in Medicine or Physiology goes to William G. Kaelin Jr. from the Dana-Farber Cancer Institute in Boston, Sir Peter J. Ratcliffe from the Francis Crick Institute in London and Gregg L. Semenza from the Johns Hopkins Institute for Cell Engineering in Baltimore.

They are being honored “for their discoveries how cells perceive the availability of oxygen and adapt to it,” announced the Nobel Prize Committee at the Karolinska Institute on Monday in Stockholm.

The researchers have succeeded in deciphering the mechanism that regulates the activity of genes in response to the different oxygen supply in cells and tissues. The best-known reaction to a lack of oxygen, for example, is the increased synthesis of erythropoietin (EPO), which stimulates erythropoiesis.

HIF is a central element

The central element here is the protein complex HIF (hypoxia-inducible factor), which Semenza discovered in the early 1990s. Part of it is HIF-1-alpha, a factor that binds to DNA and thus regulates, among other things, EPO production in the kidneys. Together with Ratcliffe, Semenza researched the regulation of the EPO gene in more detail, which is important for example in the development of anemia or for mountaineers.

The cancer researcher Kaelin was particularly interested in the inherited Von Hippel Lindau Syndrome (VHL), in which the mutated gene, a tumor suppressor gene, controls the response to hypoxia.

As a result, it turned out that the response to the respective oxygen concentration requires an interaction between the VHL gene and its protein product and the HIF-1-alpha.

Under physiological oxygen conditions, HIF-1-alpha is broken down in cooperation with the VHL complex in the proteasomes, the cell's waste churn, in a relatively short time. If, on the other hand, the oxygen concentration drops and hypoxia occurs, HIF-1-alpha is protected from degradation and, together with a second factor, can bind to specific sites in the DNA of the cell nucleus.

Regulation of gene activity

The locations on the DNA of the EPO gene are designated with the abbreviation HRE, which stands for "hypoxia / hormone response element". The regulation of gene activity runs through it. The stability of HIF-1-alpha is controlled by the enzyme proline hydroxylase, which marks HIF by hydroxylation and thereby initiates its degradation.

As Professor Randall S. Johnson of the University of Cambridge and the Karolinska Institute in Stockholm said at the announcement, the winners have discovered an elegant switch. Today at least 300 genes are known that contain the HRE region. "All are regulated by HIF so that cells and tissues can adapt to the constantly changing oxygen levels."

These genes include the protein VEGF (vascular endothelial growth factor), which regulates the formation of new blood vessels and against which antibodies are already available for therapy, and of course for EPO. Almost all the genes of the enzymes involved in glycolysis are also included.

Findings used for drug development

The disorders for which the activity of HIF is of pathophysiological importance include not only anemia and cancer - via the formation of new blood vessels - but also strokes, myocardial infarction, infections and impaired wound healing. The knowledge gained is already being used for the development of medicines.

It is about increasing the HIF-1-alpha level, for example in order to treat patients with anemia. Attempts are made to achieve this by developing inhibitors of hydroxylase. Such HIF inhibitors have already reached the phase III clinical stage.

Another strategy is to use drugs that lower these levels in the treatment of cancer patients. Such HIF-2-alpha antagonists are being tested in phase II for kidney and CNS tumors, among other things.

Johnson: "This year's three Laurates have expanded our knowledge of how physiological reactions make life possible in the first place."