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Cycling hypoxia selects for constitutive HIF stabilization
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Cycling hypoxia selects for constitutive HIF stabilization
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Paper
Cycling hypoxia selects for constitutive HIF stabilization
2020
Overview
Abstract Tumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) in tumor cells are stabilized in response to low levels of oxygen and induce angiogenesis to re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, however, HIF-α stabilization becomes constitutive even under normoxia, a condition known as pseudohypoxia. Herein, we develop a mathematical model that predicts the effects of fluctuating levels of oxygen availability on stabilization of HIF-α and its client proteins based on fitness. The model shows that facultative regulation of HIF-α always promotes greater cell fitness than constitutive regulation. However, cell fitness is nearly identical regardless of HIF-α regulation strategy when there are rapid periodic fluctuations in oxygenation. Furthermore, the model predicts that stochastic changes in oxygenation favor facultative HIF-α regulation. We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia. Competing Interest Statement The authors have declared no competing interest.
Publisher
Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
Subject
