糖原合酶激酶3(GSK3)介导的胰岛素对糖原 合酶2(GYS2)的抑制调节

本文基于Hill 动力学与 Michaelis-Menten 方程，建立理论模型研究肝癌(HCC)进展过程的微环境中，糖原合酶激酶3(GSK3)介导的胰岛素对糖原代谢的抑制调节，以及 P53 蛋白恢复调节糖原代谢异常的作用。分析了胰岛素激活 AKT 激酶影响 GYS2 磷酸化/去磷酸化转变的昼夜节律性，以及 P53 通过抑制 AKT，对 GYS2 磷酸化/去磷酸化转变的昼夜节律性异常的调节恢复特性。研究发现，胰岛素激活并提升 AKT 的表达水平，经过 AKT 的催化作用，GSK3 的表达被抑制减弱，进而增强了 GYS2 的磷酸化和失活。在胰岛素浓度较低的情况下，GYS2 去磷酸化激活的昼夜节律性会被改变，进而改变了 GYS2 昼夜节律的合成规律。在较高胰岛素浓度条件下，去磷酸化的 GYS2(dGYS2) 随时间演变的周期振荡性会被极大地改变，GYS2 昼夜节律的合成规律被破坏。改变 P53 的表达水平，我们发现，P53 对较低和较高胰岛素浓度条件下 dGYS2 异常的昼夜节律演化性，有明显的调节恢复作用。通过 P53 的调节，dGYS 随时间演化异常紊乱的昼夜节律性被还原，GYS2 恢复昼夜节律的合成。理论结果符合实验，并进一步分析了 GSK3 介导的胰岛素调节 GYS2 磷酸化/去磷酸化转变的昼夜节律性的调节机理，以及 P53 对GYS2 磷酸化/去磷酸化转变异常的调节恢复特性，进而揭示了 HCC 发生发展的一种致癌、抑癌机理，可为设计阻断致癌转变的通路治疗方案提供理论依据。

Glycogen synthase kinase 3 (GSK3) mediated inhibitory regulation of glycogen synthase 2 (GYS2) by insulin

In this paper, based on Hill kinetics and Michaelis-Menten equation, we built a theoretical model to study in the microenvironment of hepatocellular carcinoma(HCC), glycogen synthase kinase 3 (GSK3)-mediated insulin inhibition of glycogen metabolism, and P53 restores and regulates abnormal glycogen metabolism. We analyzed that insulin activation of PI3K-AKT-mTOR signaling pathway affects the circadian rhythm of GYS2 phosphorylation/dephosphorylation transition. We also investigated the restoration of circadian rhythm regulation of GYS2 phosphorylation/dephosphorylation transition by P53 through the AKT-MDM2-P53-PTEN signaling pathway. It was found that under different insulin concentration conditions, the AKT concentration gradually increased over time and reached a larger stable value, which indicated that AKT was activated and reached a certain level of expression. In the process of insulin-stimulating glycogen synthesis, insulin activates AKT by stimulating the PI3K kinase, and a larger insulin concentration greatly increases the expression level of AKT. As a result of the catalysis of AKT, GSK3 kinase is inhibited. Because of the inhibitory effect of AKT on GSK3, GSK3 presents a lower expression level under higher insulin concentration conditions. By investigating the evolution characteristics of GYS2 dephosphorylation (dGYS2) state (GYS2 activated state) over time under different insulin concentration conditions, we found that under conditions of appropriate insulin concentration (50nM), dGYS2 shows the oscillation characteristics that evolve with a relatively stable time period. When the insulin concentration is further reduced (~1nM), the period of dGYS2 evolution over time almost completely changes. When the insulin concentration is high (~250nM), the oscillation amplitude of dGYS2 gradually disappears over time, and the periodicity is completely changed. This indicates that when the insulin concentration is too high, the circadian rhythm of dGYS2 activation will be greatly changed, and the circadian rhythm of liver glycogen synthesis will be destroyed, which will lead to abnormal glycogen metabolism in the liver. By the regulation of P53, the originally disordered dGYS evolves over time, with the increase or decrease of P53, the periodicity of the dGYS2 circadian rhythm is gradually restored. It implied that P53 can significantly regulate and restore the abnormal circadian rhythm of dGYS2. The theoretical results are consistent with the experiment, and further analyze the GSK3-mediated insulin regulation mechanism of the circadian rhythm of GYS2 phosphorylation/dephosphorylation transition, and P53''s ability to regulate and restore abnormal GYS2 phosphorylation/dephosphorylation transition, which reveals a carcinogenic and anti-tumor mechanism of the occurrence and development of HCC. It can provide a theoretical basis for designing pathway treatment plan that block carcinogenic transformation.