How cells sense and adapt to oxygen availability
The Nobel Prize in Physiology or Medicine for 2019 is awarded to William Kaelin, Jr., Sir Peter Ratcliffe, and Gregg Semenza.
The need for oxygen to sustain life has been understood since the onset of modern biology; but the molecular mechanisms underlying how cells adapt to variations in oxygen supply were unknown until the prize-winning work described here.
Animal cells undergo fundamental shifts in gene expression when there are changes in the oxygen levels around them.
These changes in gene expression alter cell metabolism, tissue re-modeling, and even organismal responses such as increases in heart rate and ventilation.
In studies during the early 1990’s, Gregg Semenza identified, and then in 1995 purified and cloned, a transcription factor that regulates these oxygen-dependent responses.
He named this factor HIF, for Hypoxia Inducible Factor, and showed that it consists of two components: one a novel and oxygen-sensitive moiety, HIF-1α, and a second, previously identified and constitutively expressed and non-oxygen-regulated protein known as ARNT.
William Kaelin, Jr. was in 1995 engaged in the study of the von Hippel-Lindau tumor suppressor gene, and after isolation of the first full-length clone of the gene showed that it could suppress tumor growth in VHL mutant tumorigenic cell lines.
Ratcliffe then demonstrated in 1999 that there was an association between VHL and HIF-1α, and that VHL regulated HIF-1α post-trans-lational and oxygen-sensitive degradation.
Finally, the Kaelin and Ratcliffe groups simultaneously showed that this regulation of HIF-1α by VHL depends on hydroxylation of HIF-1α, a covalent modification that is itself dependent on oxygen.
Through the combined work of these three laureates it was thus demonstrated that the response by gene expression to changes in oxygen is directly coupled to oxygen levels in the animal cell, allowing immediate cellular responses to occur to oxygenation through the action of the HIF transcription factor.