Computational Model of MicroRNA Control of HIF-VEGF Pathway: Insights into the Pathophysiology of Ischemic Vascular Disease and Cancer
Fig 5
Let-7 and AGO1 mutually control each other in hypoxia.
(A) Varying the cellular AGO1 abundance by antagonizing or overexpressing its mRNA changes the let-7 availability. (B) Let-7s that are in association with AGO1 are less prone to degradation, so a decrease in the binding strength of let-7 toward AGO1 causes more let-7 to be degraded. Consequently, (C) let-7-mediated activity including AGO1 repression is downregulated, allowing additional AGO1 protein synthesis. (B-C) Association rate of AGO1 and let-7 (kforward) is adjusted to 10%, 20%, and 50% of its original value respectively in the comparisons. (D) AGO1 overexpression leads to an early upstroke in its time course profile but its steady state level changes insignificantly. (E) After 4 hours, almost all the additional AGO1 mRNAs (e.g. 0.01 μM and 0.04 μM) being introduced in the beginning are fully shuttled into the p-body to become inaccessible for translation. (F) In hypoxia, VEGF mRNA released from miRISC, in combination with HIF induction, boosts the pool of free form VEGF mRNA. A simulated AGO1 overexpression rescues the drop in miRISC level and drives free form VEGF mRNA back into miR-mediated repression. (A, D-F) The model assumes that in AGO1 silencing, siRNA binds AGO1 mRNA potently with a Kd of 1 nM; AGO1 overexpression is simplified as an increase of certain amount in the initial concentration of AGO1 mRNA.