KRAB型锌指蛋白PITA和PISA与p53介导的细胞代谢调控关系研究

The tumor suppressor p53 is involved in the regulation of multiple cellular outputs including cell cycle arrest, cell apoptosis and cell metabolism. Recent studies showed that the ability of p53 to control cell metabolism contributes to its tumor suppressor activity. p53 can transactivate the expression of TIGAR and SCO2 to regulate the balance between oxidative phosphorylation and glycolysis. p53 can be activated upon the response to glucose abnormality and oxidative stress. So far, few p53 regulators have been shown to participate in selective control of p53-mediated cell metabolism and how p53-mediated metabolism is negatively regulated remains unknown. We identified that the KRAB-type zinc finger proteins PITA (p53 inhibitor on TIGAR activation) and PISA (p53 inhibitor on SCO2 activation) can interact with p53 and inhibits the p53-mediated transcription of TIGAR and SCO2, respectively. In this project,we will investigate the molecular mechanism by which p53-mediated metabolism is negatively regulated by PITA and PISA, and explore theire functions in cell metabolism. We will also elucidate how PITA and PISA are regulated in reponse to metabolic stress and their functional relevance with tumor development. The project will contribute to deepen the understandings of how p53-mediated cell metabolism is regulated and might establish novel functional linkage between KRAB-type zinc finger protein family and the selective control of the famous tumor suppressor p53.

抑癌蛋白p53调控细胞周期阻滞、凋亡、代谢等多种细胞学过程。近年研究显示，p53调节细胞代谢的能力在其抑癌基因活性中具有重要地位，p53通过调节TIGAR与SCO2表达维持氧化磷酸化与糖酵解的平衡，应答和调控葡萄糖代谢与氧化应激。但是，特定时空条件下p53介导的细胞代谢如何受到选择性调控尚未见报道。我们通过筛选鉴定到KRAB型锌指蛋白PITA和PISA可结合p53并分别特异性地抑制p53对代谢靶基因TIGAR和SCO2的转录。本项目将深入研究它们调控代谢靶基因的选择性机制、对p53介导的细胞呼吸与代谢的调控功能，揭示代谢应激信号对二者的调控作用及机制，明确PITA、PISA 调控细胞代谢的时空条件及与肿瘤发生发展的关系。项目将在揭示p53-代谢通路的上游调控分子方面获得原创性认识，有助于阐明KRAB锌指蛋白家族在选择性决定p53下游细胞学效应中的重要地位。

抑癌蛋白p53调控细胞周期阻滞、凋亡、代谢等多种细胞学过程。近年研究显示，p53调节细胞代谢的能力在其抑癌基因活性中具有重要地位，p53通过调节TIGAR与SCO2表达维持氧化磷酸化与糖酵解的平衡，应答和调控葡萄糖代谢与氧化应激。但是，特定时空条件下p53介导的细胞代谢如何受到选择性调控尚未见报道。我们通过筛选鉴定到KRAB型锌指蛋白PITA和PISA可结合p53并分别特异性地抑制p53对代谢靶基因TIGAR和SCO2的转录。本项目将深入研究它们调控代谢靶基因的选择性机制、对p53介导的细胞呼吸与代谢的调控功能，揭示代谢应激信号对二者的调控作用及机制，明确PITA、PISA调控细胞代谢的时空条件及与肿瘤发生发展的关系。项目将在揭示p53-代谢通路的上游调控分子方面获得原创性认识，有助于阐明KRAB锌指蛋白家族在选择性决定p53下游细胞学效应中的重要地位。