کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
4498137 1318966 2009 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Gene regulation in response to graded hypoxia: The non-redundant roles of the oxygen sensors PHDPHD and FIH in the HIF pathway
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم کشاورزی و بیولوژیک علوم کشاورزی و بیولوژیک (عمومی)
پیش نمایش صفحه اول مقاله
Gene regulation in response to graded hypoxia: The non-redundant roles of the oxygen sensors PHDPHD and FIH in the HIF pathway
چکیده انگلیسی

Hypoxia Inducible Factor (HIF), being the master protein involved in adaptation to low pO2, plays a major role in many physiological and pathological phenomena: development, inflammation, ischemia and cancer. Prolyl hydroxylase (PHDPHD) and factor inhibiting HIF (FIH) are the two oxygen sensors that regulate the HIF pathway. Here we model the regulatory dynamics in an oxygen gradient by a system of differential equations. A part of the work consists in a qualitative analysis, driven independently of the values of the parameters, which explains the non-redundant functional roles of FIH and PHDPHD. In a second part, we use biological experiments to fit the model in a physiologically relevant context and run simulations. Simulation results are confronted with success to independent biological experiments. The combination of biological data and mathematical analysis stresses that FIH is a fine modulator determining whether a given gene should be induced in mildly or in strongly hypoxic areas. Moreover it gives access to other functional predictions that are not directly accessible by pure experiments, for instance the stoichiometry of prolyl-hydroxylation on HIF, and the switch-like properties of the system. Availability: an interactive simulation interface is available at http://sdi.ljad.free.fr/spip.php?article111.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Theoretical Biology - Volume 259, Issue 2, 21 July 2009, Pages 304–316
نویسندگان
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