摘要
细胞死亡是生物体内的一种普遍现象,它在生物体的发育、成熟以及多种疾病的发生和发展中扮演着至关重要的角色.p53作为关键的肿瘤抑制因子,在多种细胞程序性死亡过程中发挥核心作用.本文总结了近年来的研究成果,深入阐述了包括细胞凋亡、坏死性凋亡、焦亡、铁死亡,铜死亡和自噬在内的不同细胞死亡方式的分子机制,并且详细探讨了p53调控这些细胞死亡方式的作用机理.此外,我们还讨论了目前p53在调控细胞死亡信号领域中所面临的挑战和需要进一步探究的问题.本文旨在从新的视角理解细胞命运决定机制,为癌症和相关疾病的治疗带来新的思考.
Cell death is a ubiquitous biological process in organisms.It plays a crucial role in development and growth and is closely associated with the onset and progression of various diseases.It can occur through various pathways,including apoptosis,necroptosis,pyroptosis,ferroptosis,autophagy and more recently identified cuproptosis.Cancer cells often escape from cell death,leading to uncontrolled proliferation.Therefore,understanding the molecular mechanisms of cell death can contribute to the development of targeted therapies for cancer cells.p53,known as the“guardian of the genome”,is crucially involved in maintaining cellular stability.It is a transcription factor that responds to various cellular stresses,such as DNA damage,nucleolar perturbation,hypoxia,and oncogene activation,and regulates the expression of target genes involved in cell death.Due to the complexity of the mechanisms by which p53 regulates cell death,our understanding of it remains limited.Therefore,further exploration of the role of p53 in these pathways is crucial for the development of new cancer therapies.In this review,we provide an overview of p53ʹs involvement in cell death and draw on literature that explores the molecular mechanisms of p53 in various cell death types.It examines the mechanisms by which p53 executes its functions and how these mechanisms are implicated in different diseases,particularly in cancer.Studies have revealed that p53 regulates cell death through transcriptional activation of genes and direct protein interactions,affecting processes including apoptosis,necroptosis,pyroptosis,ferroptosis,cuproptosis,autophagy,and possibly other forms.The role of p53 in apoptosis involves regulating the expression of death receptors and BCL-2 family proteins,while also translocating to mitochondria to directly engage in the process.In addition,p53 modulates the balance between apoptosis and necroptosis by regulating mitochondrial ROS and the RIPK1/RIPK3 complex.Pyroptosis,characterized by caspase activation and GSDMD cleavage,is influenced by p53 through the regulation of NLRP3 inflammasomes and GSDME expression.In ferroptosis,a form of cell death dependent on iron and lipid peroxidation,p53 modulates various metabolic pathways,such as suppressing SLC7A11 and promoting ALOX12,to enhance or inhibit this process.Cuproptosis,which is dependent on copper accumulation,is also regulated by p53.This newly identified metabolic form of cell death will be an important area for future research.Despite significant advancements in understanding the mechanisms,regulation,and therapeutic implications of p53-regulated cell death in recent years,there remain several challenges.First,it is crucial to figure out how to precisely activate p53 in tumor cells to achieve the goal of‘reduced toxicity and enhanced efficacy’,as well as how to overcome resistance to p53 agonists in these cells.Second,p53 retains the ability to sustain cell survival under certain stress conditions,such as promoting DNA damage repair or inhibiting ROS and ferroptosis.In the process of cancer treatment,how to suppress p53-mediated adaptive survival pathways in tumor cells is also an important direction for future research.Finally,most current research focuses on the regulatory relationship between wild-type p53 and cell death.However,p53 is mutated in approximately 50%of human cancers,necessitating further investigation into how p53 mutants regulate cell death.In addition,from a mechanistic perspective,p53 not only induces apoptosis but also regulates various forms of programmed cell death.Tumors often evolve resistance to apoptosis,which provides new opportunities for developing antitumor strategies that utilize the p53 signaling pathway to induce different forms of programmed cell death in cancer cells.
作者
甘雨
周祥
Yu Gan;Xiang Zhou(Institutes of Biomedical Sciences,Fudan University,Shanghai 200032,China;Fudan University Shanghai Cancer Center,Shanghai 200032,China;Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China)
出处
《科学通报》
北大核心
2025年第15期2319-2332,共14页
Chinese Science Bulletin
基金
国家自然科学基金(82472714,82273098,82403120)
国家资助博士后研究人员计划(GZC20230494)资助。
作者简介
联系人:周祥,E-mail:xiangzhou@fudan.edu.cn。
