title: A computational model of intracellular oxygen sensing by hypoxia-inducible factor HIF1 alpha.
abstract: 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 HIF1alpha 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.
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, 613 Traylor Bldg, 720 Rutland Avenue, Baltimore, MD 21205, USA. aqutub@jhu.edu
authors.forename: Amina A
authors.initials: AA
authors.lastname: Qutub
authors.forename: Aleksander S
authors.initials: AS
authors.lastname: Popel
mesh_terms: D001205:Ascorbic Acid / Q000378:metabolism; D015687:Cell Hypoxia; D003198:Computer Simulation; D019587:Dietary Supplements; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D011393:Procollagen-Proline Dioxygenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D001205:Ascorbic Acid; D010100:Oxygen