Department of Mathematics, Shanghai University, Shanghai, PR China.
PLoS One. 2012;7(9):e43908. doi: 10.1371/journal.pone.0043908. Epub 2012 Sep 18.
MiRNAs, which are a family of small non-coding RNAs, regulate a broad array of physiological and developmental processes. However, their regulatory roles have remained largely mysterious. E2F is a positive regulator of cell cycle progression and also a potent inducer of apoptosis. Positive feedback loops in the regulation of Rb-E2F pathway are predicted and shown experimentally. Recently, it has been discovered that E2F induce a cluster of miRNAs called miR449. In turn, E2F is inhibited by miR449 through regulating different transcripts, thus forming negative feedback loops in the interaction network. Here, based on the integration of experimental evidence and quantitative data, we studied Rb-E2F pathway coupling the positive feedback loops and negative feedback loops mediated by miR449. Therefore, a mathematical model is constructed based in part on the model proposed in Yao-Lee et al. (2008) and nonlinear dynamical behaviors including the stability and bifurcations of the model are discussed. A comparison is given to reveal the implication of the fundamental differences of Rb-E2F pathway between regulation and deregulation of miR449. Coherent with the experiments it predicts that miR449 plays a critical role in regulating the cell cycle progression and provides a twofold safety mechanism to avoid excessive E2F-induced proliferation by cell cycle arrest and apoptosis. Moreover, numerical simulation and bifurcation analysis shows that the mechanisms of the negative regulation of miR449 to three different transcripts are quite distinctive which needs to be verified experimentally. This study may help us to analyze the whole cell cycle process mediated by other miRNAs more easily. A better knowledge of the dynamical behaviors of miRNAs mediated networks is also of interest for bio-engineering and artificial control.
miRNAs 是一类小的非编码 RNA，调节广泛的生理和发育过程。然而，它们的调节作用在很大程度上仍然是神秘的。E2F 是细胞周期进程的正调节剂，也是凋亡的有力诱导剂。在 Rb-E2F 途径的调节中预测并实验证明了正反馈环。最近，发现 E2F 诱导了一组称为 miR449 的 miRNAs。反过来，miR449 通过调节不同的转录本抑制 E2F，从而在相互作用网络中形成负反馈环。在这里，基于实验证据和定量数据的整合，我们研究了 Rb-E2F 途径，该途径将由 miR449 介导的正反馈环和负反馈环结合在一起。因此，部分基于 Yao-Lee 等人提出的模型（2008 年）构建了一个数学模型，并讨论了模型的非线性动力学行为，包括稳定性和分叉。给出了一个比较，以揭示 miR449 对 Rb-E2F 途径的调节和去调节的基本差异的含义。与实验一致，它预测 miR449 在调节细胞周期进程中起着关键作用，并通过细胞周期阻滞和凋亡提供了双重安全机制来避免过度的 E2F 诱导的增殖。此外，数值模拟和分叉分析表明，miR449 对三个不同转录本的负调节机制非常独特，需要实验验证。这项研究可能有助于我们更容易地分析其他 miRNAs 介导的整个细胞周期过程。miRNAs 介导的网络的动态行为的更好了解也对生物工程和人工控制感兴趣。
