Regulation of cytoplasmic polyadenylation can generate a bistable switch
Regulation of cytoplasmic polyadenylation can generate a bistable switch
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DOI：
10.1186/1752-0509-6-12
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发表时间：
2012-02-15
影响因子：
--
通讯作者：
Shouval, Harel Z.
中科院分区：
文献类型：
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作者：
Aslam, Naveed;Shouval, Harel Z.
背景：某些mrna的翻译效率可以通过起始前的细胞质聚腺苷化过程来调节。翻译调节因子控制聚腺苷化过程，这种调节依赖于其翻译后修饰，例如磷酸化。胞质聚腺苷化结合蛋白（CPEB1）就是这样一种翻译调节因子，它通过与胞质聚腺苷化元件（CPE）结合来调节一些mrna的翻译。胞质聚腺苷化过程可以通过CPEB1的磷酸化或去磷酸化状态来开启或关闭。一个具体的例子可能是通过CPEB1的磷酸化/去磷酸化循环调节钙/钙调素依赖性蛋白激酶II （α CaMKII）的翻译。结果：在这里，我们发现CPEB1介导的α CaMKII mRNA的聚腺苷化可以导致双稳态开关机制。调节聚腺苷化的开关是基于α - CaMKII的双状态模型及其与CPEB1的相互作用。基于基本生化动力学的高维非线性常微分方程组可以描述聚腺苷酸化环的动力学特性。在这里，我们将这个高维系统简化为近似的低维系统，可以提供对原系统的动力学和不动点的理解。这些简化的方程可以在不使用复杂的数值跟踪算法的情况下建立解析分岔图，并且可以进一步直观地了解系统双稳定性的参数依赖性。结论：本研究提供了一种系统的方法来简化、近似和分析基于翻译/激活的正反馈回路。这项工作展示了如何提取低维系统，这些系统可用于获得系统不动点的解析解并描述系统的动力学。本文所采用的方法对许多分子网络的形成和分析具有普遍的适用性。
Background: Translation efficiency of certain mRNAs can be regulated through a cytoplasmic polyadenylation process at the pre-initiation phase. A translational regulator controls the polyadenylation process and this regulation depends on its posttranslational modifications e. g., phosphorylation. The cytoplasmic polyadenylation binding protein (CPEB1) is one such translational regulator, which regulates the translation of some mRNAs by binding to the cytoplasmic polyadenylation element (CPE). The cytoplasmic polyadenylation process can be turned on or off by the phosphorylation or dephosphorylation state of CPEB1. A specific example could be the regulation of Calcium/Calmodulin-dependent protein kinase II (alpha CaMKII) translation through the phosphorylation/dephosphorylation cycle of CPEB1.Result: Here, we show that CPEB1 mediated polyadenylation of alpha CaMKII mRNA can result in a bistable switching mechanism. The switch for regulating the polyadenylation is based on a two state model of alpha CaMKII and its interaction with CPEB1. Based on elementary biochemical kinetics a high dimensional system of non-linear ordinary differential equations can describe the dynamic characteristics of the polyadenylation loop. Here, we simplified this high-dimensional system into approximate lower dimension system that can provide the understanding of dynamics and fixed points of original system. These simplified equations can be used to develop analytical bifurcation diagrams without the use of complex numerical tracking algorithm, and can further give us intuition about the parameter dependence of bistability in this system.Conclusion: This study provides a systematic method to simplify, approximate and analyze a translation/activation based positive feedback loop. This work shows how to extract low dimensional systems that can be used to obtain analytical solutions for the fixed points of the system and to describe the dynamics of the system. The methods used here have general applicability to the formulation and analysis of many molecular networks.