期刊
JOURNAL OF CELL SCIENCE
卷 119, 期 16, 页码 3467-3480出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.03087
关键词
computational modeling; mathematical modeling; oxygen sensing; hypoxic response
类别
资金
- NHLBI NIH HHS [F32 HL085016-02, HL18292, HL79653, R01 HL018292, R01 HL079653, F32 HL085016-01] Funding Source: Medline
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 O-2 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 O-2 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 HIF1 alpha 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.
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