Modeling miRNA Regulation in Cancer Signaling Systems: miR-34a Regulation of the p53/Sirt1 Signaling Module
MicroRNAs (miRNAs) are a family of small regulatory RNAs whose function is to regulate the activity and stability of specific messenger RNA targets through posttranscriptional regulatory mechanisms. Most of the times signaling systems involving miRNA modulation are not linear pathways in which a certain transcription factor activate the expression of miRNAs that posttranscriptionally represses targeting proteins, but complex regulatory structures involving a variety of feedback-loop architectures.
In this book chapter, we define, discuss, and apply a Systems Biology approach to investigate dynamical features of miRNA regulation, based on the integration of experimental evidences, hypotheses, and quantitative data through mathematical modeling. We further illustrate the approach using as case study the signaling module composed by the proteins p53, Sirt1, and the regulatory miRNA miR-34a. The model was used not only to investigate different possible designs of the silencing mechanism exerted by miR-34a on Sirt1 but also to simulate the dynamics of the system under conditions of (pathological) deregulation of its compounds.
Key wordsSystems biology p53 miR-34a Sirt1 DBC1 ODE model Silencing posttranscriptional regulation Mathematical modeling Power-law model
J.V. and X.L. are funded by the German Federal Ministry of Education and Research (BMBF) as part of the project CALSYS-FORSYS under contract 0315264 (www.sbi.uni-rostock.de/calsys). O.W. was supported by the Helmholtz Foundation as part of the Systems Biology Network.
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