Three autocrine feedback loops determine HIF1α expression in chronic hypoxia

Hypoxia occurs in cancer, prolonged exercise, and long-term ischemia with durations of several hours or more, and the hypoxia-inducible factor 1 (HIF1) pathway response to these conditions differs from responses to transient hypoxia. We used computational modeling, validated by experiments, to gain a quantitative, temporal understanding of the mechanisms driving HIF1 response. To test the hypothesis that HIF1α protein levels during chronic hypoxia are tightly regulated by a series of molecular feedbacks, we took into account protein synthesis and product inhibition, and analyzed HIF1 system changes in response to hypoxic exposures beyond 3 to 4 h. We show how three autocrine feedback loops together regulate HIF1α hydroxylation in different microenvironments. Results demonstrate that prolyl hydroxylase, succinate and HIF1α feedback determine intracellular HIF1α levels over the course of hours to days. The model provides quantitative insight critical for characterizing molecular mechanisms underlying a cell's response to long-term hypoxia.