Abstract
The Nobel Prize in Physiology or Medicine for the year 2019 has been awarded to three scientists, namely William G Kaelin, Gregg Semenza and Peter J Ratcliffe, for their research work leading to an understanding of the mechanism used by living cells to sense the level of O2. They discovered the occurrence of a molecule called hypoxia-inducible factor (HIF) within the cells and demonstrated that under normoxic condition, HIF undergoes hydroxylation and ubiquitination followed by its degradation in proteasome. Under conditions of hypoxia, HIF becomes active and binds to hypoxia response element available within hundreds of target genes leading to their activation to overcome the problems due to hypoxia. Any aberration in this process of degradation and activation of HIF may cause a variety of diseases, so drugs based on BIF stabilizers/inhibitors have been developed and are under different stages of clinical trials.
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References
Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE (1991) Hypoxia inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci USA 88:5680–5684
Wang GL, Semenza GL (1993) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci USA 90:4304–4308
Semenza GL (2010) Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med 2:336–361
Wang GL, Semenza GL (1995) Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270:1230–1237
Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514
Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia de novo protein synthesis binds the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12:5447–5454
Pugh CW, Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ (1997) Activation of hypoxia-inducible factor-1; definition of regulatory domains within the α subunit. J Biol Chem 272:11205
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468
Epstein ACR, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson M, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54
Mole DR, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Regulation of HIF by the von Hippel-Lindau tumour suppressor: implications for cellular oxygen sensing. IUBMB Life 52:43–47
Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 2001:2675–2686
Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML et al (2002) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16:1466–1471
Semenza GL (2019) Pharmocological targeting of hypoxia inducible factors. Annu Rev Pharmacol Toxicol 59:379–403
Jakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Heberstreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Science 292:468–472
Kaelin WG Jr, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30:393–402
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Significance statement The 2019 Nobel Prize for Medicine has been awarded for the discovery of hypoxia-inducible factor, which gets degraded under normoxic conditions, but activates several genes during hypoxia. This resulted in development of drugs for human diseases.
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Gupta, P.K. How does Cell Machinery Sense and Deal with Hypoxia? The 2019 Nobel Prize for Medicine. Proc. Natl. Acad. Sci., India, Sect. B Biol. Sci. 90, 945–950 (2020). https://doi.org/10.1007/s40011-020-01182-2
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DOI: https://doi.org/10.1007/s40011-020-01182-2