文章：

蛋白激酶在p53 Sestrin信号通路中的重要作用

The Important Role of Protein Kinases in the p53 Sestrin Signaling Pathway

原文发布日期：13 November 2023

DOI: 10.3390/cancers15225390

类型: Article

开放获取: 是

英文摘要：

p53, a crucial tumor suppressor and transcription factor, plays a central role in the maintenance of genomic stability and the orchestration of cellular responses such as apoptosis, cell cycle arrest, and DNA repair in the face of various stresses. Sestrins, a group of evolutionarily conserved proteins, serve as pivotal mediators connecting p53 to kinase-regulated anti-stress responses, with Sestrin 2 being the most extensively studied member of this protein family. These responses involve the downregulation of cell proliferation, adaptation to shifts in nutrient availability, enhancement of antioxidant defenses, promotion of autophagy/mitophagy, and the clearing of misfolded proteins. Inhibition of the mTORC1 complex by Sestrins reduces cellular proliferation, while Sestrin-dependent activation of AMP-activated kinase (AMPK) and mTORC2 supports metabolic adaptation. Furthermore, Sestrin-induced AMPK and Unc-51-like protein kinase 1 (ULK1) activation regulates autophagy/mitophagy, facilitating the removal of damaged organelles. Moreover, AMPK and ULK1 are involved in adaptation to changing metabolic conditions. ULK1 stabilizes nuclear factor erythroid 2-related factor 2 (Nrf2), thereby activating antioxidative defenses. An understanding of the intricate network involving p53, Sestrins, and kinases holds significant potential for targeted therapeutic interventions, particularly in pathologies like cancer, where the regulatory pathways governed by p53 are often disrupted.

摘要翻译： 

p53作为一种关键的肿瘤抑制因子和转录因子，在维持基因组稳定性及协调细胞应对多种应激反应（如凋亡、细胞周期阻滞和DNA修复）中发挥核心作用。Sestrins是一类进化保守蛋白，作为连接p53与激酶调控的抗应激反应的关键介质，其中Sestrin 2是该蛋白家族中被研究最深入的成员。这些反应涉及细胞增殖的下调、对营养可用性变化的适应、抗氧化防御的增强、自噬/线粒体自噬的促进以及错误折叠蛋白的清除。Sestrins通过抑制mTORC1复合物来减少细胞增殖，同时依赖Sestrin激活的AMP活化激酶（AMPK）和mTORC2则支持代谢适应。此外，Sestrin诱导的AMPK与Unc-51样激酶1（ULK1）激活可调控自噬/线粒体自噬，促进受损细胞器的清除。同时，AMPK和ULK1还参与适应不断变化的代谢条件。ULK1能稳定核因子E2相关因子2（Nrf2），从而激活抗氧化防御机制。深入理解p53、Sestrins及激酶之间复杂的调控网络，对于开发靶向治疗策略具有重要潜力，特别是在癌症等疾病中——这些疾病的p53调控通路常发生紊乱。

原文链接：

The Important Role of Protein Kinases in the p53 Sestrin Signaling Pathway