摘要
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.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.
In this paper, based on Hill kinetics and Michaelis-Menten equation, we built a theoretical model to studyin 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 the influences of insulin activation of PI3 K-AKT-mTOR signaling pathway on the circadian rhythm of GYS2 phosphorylation/dephosphorylation transition, and 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 insulin activates and increases the expression level of AKT. As a result of the catalysis of AKT, GSK3 kinase is inhibited and weakened, which enhances the phosphorylation and inactivation of GYS2. In the case of low insulin concentration, the circadian rhythm of GYS2 dephosphorylation activation will be changed, which in turn changes the synthesis of GYS2 circadian rhythm. Under the condition of higher insulin concentration, the periodic oscillation of dephosphorylated GYS2(dGYS2) over time will be greatly changed, and the synthesis of GYS2 circadian rhythm will be destroyed. Changing the expression level of P53, we found that P53 can significantly regulate and restore the abnormal circadian evolution of dGYS2 under conditions of lower and higher insulin concentrations. By the regulation of P53, the disordered dGYS evolves over time, with the increase or decrease of P53, the periodicity of the dGYS2 circadian rhythm is gradually restored. The theoretical results are consistent with the experiments. We 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 the
作者
周圣曜
赵新军
ZHOU Sheng-Yao;ZHAO Xin-Jun(Xinjiang Laboratory of Phase Transitions and Microstructures of Condensed Matter Physics,Yi Li Normal University,Yining 835000,China;Laboratory of Micro-Nano Electro Biosensors and Bionic Devices,Yi Li Normal University,Yining 835000,China)
出处
《原子与分子物理学报》
CAS
北大核心
2022年第3期1-9,共9页
Journal of Atomic and Molecular Physics
基金
国家自然科学基金(21764015)
伊犁师范大学博士科研启动基金(2020YSBS008)。
