Molecular events that determine the functional outcome of GSK3 inhibition

决定 GSK3 抑制功能结果的分子事件

• 批准号: 510573839
• 负责人: Professorin Dr. Julia Jellusova
• 金额: --
• 依托单位: Institut für Klinische Chemie und Pathobiochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/510573839?language=en
• 关键词: Molecular; events; determine; functional; outcome

Recent years have brought a growing appreciation of the intricate links between cell signaling and metabolism. While extracellular activation results in metabolic reprograming to meet the biosynthetic and energetic needs of proliferating cells, changes in the extracellular metabolic microenvironment, the activity of metabolic enzymes or the pools of intracellular metabolites can profoundly affect cell signaling and thus cell fate and function. In our previous work we have identified the glycogen synthase kinase 3 (GSK3)/ β-catenin signaling axis to play a crucial role in coordinating B cell fate decisions with metabolic activity. We could show that GSK3 inhibition/ β-catenin accumulation enhances mitochondrial activity resulting in increased cell mass and proliferation. On the other hand, we found GSK3 inhibition/β-catenin accumulation to result in increased production of reactive oxygen species and higher susceptibility to different types of stress such as DNA damage or nutrient restriction. Interestingly, we found B cell precursors to be more sensitive to β-catenin accumulation than mature B cells. Taken together these findings argue for a context-dependent role of the GSK3/ β-catenin signaling pathway. Our aim now is to identify the signaling events that tip the balance between increased metabolic activity and cell death in GSK3-inhibited B cells, to further clarify the role of GSK3/ β-catenin in genotoxic stress responses and to provide insight into the role of β-catenin in mitochondrial metabolism. GSK3 inhibitors are safe to use in humans. A better understanding of the role of the GSK3/ β-catenin signaling network is needed in order to explore potential therapeutic use of GSK3 inhibitors in B cell malignancies.

近年来，人们越来越认识到细胞信号传导和新陈代谢之间的复杂联系。虽然细胞外激活导致代谢重编程以满足增殖细胞的生物合成和能量需求，但细胞外代谢微环境的变化、代谢酶的活性或细胞内代谢物的池可以深刻地影响细胞信号传导，从而影响细胞的命运和功能。在我们之前的工作中，我们已经确定了糖原合成酶激酶3 (GSK3)/ β-catenin信号轴在协调B细胞命运决定与代谢活性方面发挥关键作用。我们可以证明GSK3抑制/ β-catenin积累增强了线粒体活性，从而增加了细胞质量和增殖。另一方面，我们发现GSK3抑制/β-catenin积累导致活性氧的产生增加，并且对不同类型的胁迫（如DNA损伤或营养限制）更敏感。有趣的是，我们发现B细胞前体比成熟B细胞对β-catenin积累更敏感。综上所述，这些发现证明了GSK3/ β-catenin信号通路的环境依赖性作用。我们现在的目标是确定在GSK3抑制的B细胞中，改变代谢活性增加和细胞死亡之间平衡的信号事件，进一步阐明GSK3/ β-catenin在基因毒性应激反应中的作用，并提供β-catenin在线粒体代谢中的作用。GSK3抑制剂在人类中使用是安全的。为了探索GSK3抑制剂在B细胞恶性肿瘤中的潜在治疗用途，需要更好地了解GSK3/ β-catenin信号网络的作用。