Three autocrine feedback loops determine HIF1 alpha 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 HIF1 alpha 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 HIF 1 alpha hydroxylation in different microenvironments. Results demonstrate that prolyl hydroxylase, succinate and HIF1 alpha feedback determine intracellular HIF1 alpha 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.
Qutub
Amina A
AA
Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, 613 Traylor Building, 720 Rutland Avenue, Baltimore, MD 21205, USA. aqutub@jhu.edu
Popel
Aleksander S
AS
D000818:Animals; D019898:Autocrine Communication; D015687:Cell Hypoxia / Q000502:physiology*; D003198:Computer Simulation; D025461:Feedback, Physiological; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D008954:Models, Biological; D010100:Oxygen / Q000502:physiology; D011393:Procollagen-Proline Dioxygenase / Q000096:biosynthesis / Q000502:physiology*; D019802:Succinic Acid / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019802:Succinic Acid; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen