title: Role of compartmentalization on HiF-1α degradation dynamics during changing oxygen conditions: a computational approach.
abstract: HiF-1α is the central protein driving the cellular response to hypoxia. Its accumulation in cancer cells is linked to the appearance of chemoresistant and aggressive tumor phenotypes. As a consequence, understanding the regulation of HiF-1α dynamics is a major issue to design new anti-cancer therapies. In this paper, we propose a model of the hypoxia pathway, involving HiF-1α and its inhibitor pVHL. Based on data from the literature, we made the hypothesis that the regulation of HiF-1α involves two compartments (nucleus and cytoplasm) and a constitutive shuttle of the pVHL protein between them. We first show that this model captures correctly the main features of HiF-1α dynamics, including the bi-exponential degradation profile in normoxia, the kinetics of induction in hypoxia, and the switch-like accumulation. Second, we simulated the effects of a hypoxia/reoxygenation event, and show that it generates a strong instability of HiF-1α. The protein concentration rapidly increases 3 hours after the reoxygenation, and exhibits an oscillating pattern. This effect vanishes if we do not consider compartmentalization of HiF-1α. This result can explain various counter-intuitive observations about the specific molecular and cellular response to the reoxygenation process. Third, we simulated the HiF-1α dynamics in the tumor case. We considered different types of mutations associated with tumorigenesis, and we compared their consequences on HiF-1α dynamics. Then, we tested different therapeutics strategies. We show that a therapeutic decrease of HiF-1α nuclear level is not always correlated with an attenuation of reoxygenation-induced instabilities. Thus, it appears that the design of anti-HiF-1α therapies have to take into account these two aspects to maximize their efficiency.
authors.affiliation: UJF-Grenoble 1, CNRS, Laboratory TIMC-IMAG/DyCTIM, UMR 5525, La Tronche, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Bedessem
authors.affiliation: UJF-Grenoble 1, CNRS, Laboratory TIMC-IMAG/DyCTIM, UMR 5525, La Tronche, France.
authors.forename: Angélique
authors.initials: A
authors.lastname: Stéphanou
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002451:Cell Compartmentation; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015233:Models, Statistical; D009154:Mutation; D041681:NIH 3T3 Cells; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology*; D055550:Protein Stability; D059748:Proteolysis; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; C494469:VHL protein, mouse; D010100:Oxygen