TY - JOUR
T1 - A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1α
AU - Qutub, Amina A.
AU - Popel, Aleksander S.
PY - 2006/8/15
Y1 - 2006/8/15
N2 - Hypoxia-inducible factor-1, HIF1, transcriptionally activates over 200 genes vital for cell homeostasis and angiogenesis. We developed a computational model to gain a detailed quantitative understanding of how HIF1 acts to sense oxygen and respond to hypoxia. The model consists of kinetic equations describing the intracellular variation of 17 compounds, including HIF1, iron, prolyl hydroxylase, oxygen, ascorbate, 2-oxoglutarate, von Hippel Lindau protein and associated complexes. We tested an existing hypothesis of a switch-like change in HIF1 expression in response to a gradual decrease in O2 concentration. Our model predicts that depending on the molecular environment, such as intracellular iron levels, the hypoxic response varies considerably. We show HIF1-activated cellular responses can be divided into two categories: a steep, switch-like response to O2 and a gradual one. Discovery of this dual response prompted comparison of two therapeutic strategies, ascorbate and iron supplementation, and prolyl hydroxylase targeting, to predict under what microenvironments either effectively increases HIF1α hydroxylation. Results provide crucial insight into the effects of iron and prolyl hydroxylase on oxygen sensing. The model advances quantitative molecular level understanding of HIF1 pathways - an endeavor that will help elucidate the diverse responses to hypoxia found in cancer, ischemia and exercise.
AB - Hypoxia-inducible factor-1, HIF1, transcriptionally activates over 200 genes vital for cell homeostasis and angiogenesis. We developed a computational model to gain a detailed quantitative understanding of how HIF1 acts to sense oxygen and respond to hypoxia. The model consists of kinetic equations describing the intracellular variation of 17 compounds, including HIF1, iron, prolyl hydroxylase, oxygen, ascorbate, 2-oxoglutarate, von Hippel Lindau protein and associated complexes. We tested an existing hypothesis of a switch-like change in HIF1 expression in response to a gradual decrease in O2 concentration. Our model predicts that depending on the molecular environment, such as intracellular iron levels, the hypoxic response varies considerably. We show HIF1-activated cellular responses can be divided into two categories: a steep, switch-like response to O2 and a gradual one. Discovery of this dual response prompted comparison of two therapeutic strategies, ascorbate and iron supplementation, and prolyl hydroxylase targeting, to predict under what microenvironments either effectively increases HIF1α hydroxylation. Results provide crucial insight into the effects of iron and prolyl hydroxylase on oxygen sensing. The model advances quantitative molecular level understanding of HIF1 pathways - an endeavor that will help elucidate the diverse responses to hypoxia found in cancer, ischemia and exercise.
KW - Computational modeling
KW - Hypoxic response
KW - Mathematical modeling
KW - Oxygen sensing
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U2 - 10.1242/jcs.03087
DO - 10.1242/jcs.03087
M3 - Article
C2 - 16899821
AN - SCOPUS:33748774664
SN - 0021-9533
VL - 119
SP - 3467
EP - 3480
JO - Journal of cell science
JF - Journal of cell science
IS - 16
ER -