Discoveries of how cells sense oxygen win the 2019 Nobel Prize in Physiology or medicine

Abstract

The importance of oxygen to life has been recognized for hundreds of years, but how cells and tissues sense reduced oxygen levels remained elusive until the late twentieth century. The 2019 Nobel Prize in Physiology or Medicine was awarded to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza for their discovery of hypoxia-inducible factor, a key transcription factor that regulates gene expression in response to decreases in cellular oxygenation. The three scientists provided the first information about the cellular oxygen-sensing mechanism and downstream signal transduction under hypoxic conditions. Their discoveries have also paved the way for promising novel treatments for cancer, renal anemia, and inflammatory disease.

Keywords: Hypoxia-inducible factor; Nobel Prize; von hippel-Lindau (VHL) disease.

Fig. 1

Cellular regulation of hypoxia-inducible factor (HIF) activity. Intracellular oxygen level determines the accessibility of HIF-1α being hydroxylized by PHDs. In normoxia, prolyl hydroxylation of HIF-1α increases the affinity of HIF-1α for pVHL which recruits elongin B and C, CULs, and RBX1 to constitute a functional E3 ubiquitin ligase, thereby leading HIF-1α into proteasomal degradation. When oxygen becomes limited, HIF-1α is no longer hydroxylated and becomes stabilized. HIF-1α then binds to HIF-1β and the HIF-1 heterodimer binds to HRE that ultimately results in the transcriptional responses to hypoxia. Abbreviations used: HIF: hypoxia-inducible factor; PHD: prolyl hydroxylase domain; pVHL: Von Hippel–Lindau protein; CUL2: Culin 2; B: Elongin B; C: Elongin C; RBX1: RING-box protein 1; HRE: hypoxia-response element.