title: A mathematical model of HiF-1α-mediated response to hypoxia on the G1/S transition.
abstract: Hypoxia is known to influence the cell cycle by increasing the G1 phase duration or by inducing a quiescent state (arrest of cell proliferation). This entry into quiescence is a mean for the cell to escape from hypoxia-induced apoptosis. It is suggested that some cancer cells have gain the advantage over normal cells to easily enter into quiescence when environmental conditions, such as oxygen pressure, are unfavorable [43,1]. This ability contributes in the appearance of highly resistant and aggressive tumor phenotypes [2]. The HiF-1α factor is the key actor of the intracellular hypoxia pathway. As tumor cells undergo chronic hypoxic conditions, HiF-1α is present in higher level in cancer than in normal cells. Besides, it was shown that genetic mutations promoting overstabilization of HiF-1α are a feature of various types of cancers [7]. Finally, it is suggested that the intracellular level of HiF-1α can be related to the aggressiveness of the tumors [53,24,4,10]. However, up to now, mathematical models describing the G1/S transition under hypoxia, did not take into account the HiF-1α factor in the hypoxia pathway. Therefore, we propose a mathematical model of the G1/S transition under hypoxia, which explicitly integrates the HiF-1α pathway. The model reproduces the slowing down of G1 phase under moderate hypoxia, and the entry into quiescence of proliferating cells under severe hypoxia. We show how the inhibition of cyclin D by HiF-1α can induce quiescence; this result provides a theoretical explanation to the experimental observations of Wen et al. (2010) [50]. Thus, our model confirms that hypoxia-induced chemoresistance can be linked, for a part, to the negative regulation of cyclin D by HiF-1α.
authors.affiliation: UJF-Grenoble 1, CNRS, Laboratory TIMC-IMAG/DyCTIM, UMR 5525, 38041 Grenoble, France. Electronic address: Baptiste.Bedessem@imag.fr.
authors.forename: B
authors.initials: B
authors.lastname: Bedessem
authors.affiliation: UJF-Grenoble 1, CNRS, Laboratory TIMC-IMAG/DyCTIM, UMR 5525, 38041 Grenoble, France. Electronic address: Angelique.Stephanou@imag.fr.
authors.forename: A
authors.initials: A
authors.lastname: Stéphanou
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D056741:Cyclin D / Q000502:physiology; D019927:Cyclin E / Q000502:physiology; D059585:G1 Phase Cell Cycle Checkpoints / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D055641:Mathematical Concepts; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology / Q000503:physiopathology; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D056741:Cyclin D; D019927:Cyclin E; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016160:Retinoblastoma Protein; D010100:Oxygen
keywords: Cancer; Cell cycle arrest; G1/S transition; HiF-1; Hypoxia; Quiescence