基于Hill动力学与Michaelis-Menten方程,建立理论模型研究发状分裂相关增强子1(Hairy and enhancer of split 1,Hes1)调控蛋白激酶B(Protein Kinase B,AKT)-鼠双微体2(Murine Double Minute2,MDM2)-抗癌基因p53(p53)-第10号染色体缺失...基于Hill动力学与Michaelis-Menten方程,建立理论模型研究发状分裂相关增强子1(Hairy and enhancer of split 1,Hes1)调控蛋白激酶B(Protein Kinase B,AKT)-鼠双微体2(Murine Double Minute2,MDM2)-抗癌基因p53(p53)-第10号染色体缺失的磷酸酶及张力蛋白同源的基因(Phosphatase and tensin homolog deleted on chromosome ten,PTEN)通路的一种物理机制.研究发现,Hes1通过与PTEN结合抑制PTEN表达,并调控AKT信号.表明了Hes1蛋白的合成,以及Hes1与PTEN相互作用调控AKT-MDM2-p53-PTEN通路信号,将会有效地控制细胞结果.Hes1作为AKT-MDM2-p53-PTEN信号通路中上游调节的重要因素,还可以在一定程度上通过影响p53蛋白功能,改变p53对肿瘤的抑制性.理论结果可用于预测Notch通路信号异常诱导的致癌性,并进一步揭示了Notch信号通路影响细胞AKT-MDM2-p53-PTEN通路的激活机制.展开更多
The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer ons...The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.展开更多
文摘基于Hill动力学与Michaelis-Menten方程,建立理论模型研究发状分裂相关增强子1(Hairy and enhancer of split 1,Hes1)调控蛋白激酶B(Protein Kinase B,AKT)-鼠双微体2(Murine Double Minute2,MDM2)-抗癌基因p53(p53)-第10号染色体缺失的磷酸酶及张力蛋白同源的基因(Phosphatase and tensin homolog deleted on chromosome ten,PTEN)通路的一种物理机制.研究发现,Hes1通过与PTEN结合抑制PTEN表达,并调控AKT信号.表明了Hes1蛋白的合成,以及Hes1与PTEN相互作用调控AKT-MDM2-p53-PTEN通路信号,将会有效地控制细胞结果.Hes1作为AKT-MDM2-p53-PTEN信号通路中上游调节的重要因素,还可以在一定程度上通过影响p53蛋白功能,改变p53对肿瘤的抑制性.理论结果可用于预测Notch通路信号异常诱导的致癌性,并进一步揭示了Notch信号通路影响细胞AKT-MDM2-p53-PTEN通路的激活机制.
基金supported by the National Institutes of Health(NIH)grants R01CA112029 and R01CA121211a Susan G Komen Foundation grant BCTR0707731(to R.Z.)
文摘The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.
