page_title: William Kaelin Jr.
section_title: Research
hierarchical_section_title: William Kaelin Jr. / Research
caption_attribution_description: English: Nobel Prize in Physiology or Medicine 2019: How Cells Sense and Adapt to Oxygen Availability. Under normoxic conditions, Hif-1 alpha is hydroxylated at two proline residues. The protein then associates with VHL and is subsequently tagged with ubiquitin. Tagged Hif-1 alpha is then translocated to the proteasome, where it is degraded. Under hypoxic conditions, no oxygen is available for proline hydroxylation. In this situation Hif-1 alpha translocates to the cell nucleus and associates with Hif-1 beta, also termed ARNT. This complex then binds to a DNA region termed HRE (hypoxia responsive element). As a consequence target genes are transcribed. These genes are involved in the regulation of a multitude of processes, including erythropoesis, glycolysis and angiogenesis.
context_page_description: William G. Kaelin Jr. is an American Nobel Laureate physician-scientist. He is a professor of medicine at Harvard University and the Dana-Farber Cancer Institute. His laboratory studies tumor suppressor proteins.
  In 2016, Kaelin received the Albert Lasker Award for Basic Medical Research and the AACR Princess Takamatsu Award.
  He also won the Nobel Prize in Physiology or Medicine in 2019 along with Peter J. Ratcliffe and Gregg L. Semenza.
context_section_description: Following his post-doctorate, Kaelin set up a laboratory at Dana-Farber in 1993 to continue his research on tumor suppression. He had become interested in Von Hippel–Lindau disease (VHL). VHL tumors, caused by gene mutation, were known to be angiogenic, creating blood vessels that secreted erythropoietin (EPO), a hormone known to be part of the body's mechanic to react to hypoxia, or low oxygen levels in the blood. Kaelin hypothesized that there may be a connection between the formation of VHL tumors and the deficiency of the body to detect oxygen. Kaelin's research found that in VHL subjects, there were genes expressed the formation of a protein critical in the EPO process, but which the mutation suppressed. Kaelin's work aligned with that of Peter J. Ratcliffe and Gregg Semenza who separately had identified a two-part protein, hypoxia-inducible factors (HIF) that was essential to EPO production and which was triggered by oxygen levels in the blood. Kaelin's work found that the VHL protein would help regulate the HIF, and in subjects where the VHL proteins were not present, the HIF would overproduce EPO and lead to cancer. The combined work of Kaelin, Ratcliffe, and Semenza identified the pathway of how cells detect and react to oxygen levels in the blood, and have led to the development of drugs to help patients with anaemia and kidney failure.
caption: Illustration of how cells sense and adapt to oxygen availability
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