Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450003, China.
Adv Exp Med Biol. 2019;1206:127-149. doi: 10.1007/978-981-15-0602-4_6.
The tumor suppressor gene Tp53 encodes p53, a pivotal transcription factor with a broad target gene repertoire. Induction and stabilization of p53 during DNA damage and oncogene activation function to induce cell cycle arrest, apoptosis, or senescence. These actions are a failsafe to counteract carcinogenesis but Tp53 also plays a key role in regulating different aspects of cell metabolism including autophagy. Autophagy or cellular "self-eating" involves the dismantling and remodeling of cellular components, activities which are fundamental in maintaining cellular homeostasis and in supporting cell growth. After providing an historical overview of Tp53 research, the purpose of this chapter is to review the different mechanistic aspects of Tp53's role in autophagy and to highlight the key challenges which lie ahead. Tp53 functions are regulated by tight control of its cellular levels and notably, Tp53 can be both an activator or inhibitor of autophagy. Under stress conditions such as nutrient depletion or hypoxia, Tp53 contributes to autophagic activation by inhibiting mTOR signaling. Alternatively, p53 can interact with death-associated protein kinase 1 (DAPK1), acting to stabilize nuclear p53 amongst other functions including activation of the key autophagic mediator, Beclin-1. Under normal physiological conditions, Tp53 can inhibit autophagosome formation but stress conditions can also result in Tp53-mediated promotion of autophagy, demonstrating that Tp53 actions are highly context dependent. Tp53 target genes also play key opposing roles in autophagy induction or inhibition such as DRAM and TIGAR, respectively. Finally, the role of Tp53 mutants in autophagy regulation are discussed.
抑癌基因 Tp53 编码 p53，p53 是一种具有广泛靶基因谱的关键转录因子。在 DNA 损伤和癌基因激活期间，p53 的诱导和稳定作用可诱导细胞周期停滞、细胞凋亡或衰老。这些作用是对抗致癌作用的安全措施，但 Tp53 也在调节细胞代谢的不同方面发挥关键作用，包括自噬。自噬或细胞“自噬”涉及细胞成分的拆解和重塑，这些活动是维持细胞内稳态和支持细胞生长的基础。在提供 Tp53 研究的历史概述后，本章的目的是回顾 Tp53 在自噬中的作用的不同机制方面，并强调摆在面前的关键挑战。Tp53 的功能受其细胞水平的严格控制调节，特别是，Tp53 可以作为自噬的激活剂或抑制剂。在营养物质耗尽或缺氧等应激条件下，Tp53 通过抑制 mTOR 信号来促进自噬的激活。或者，p53 可以与死亡相关蛋白激酶 1（DAPK1）相互作用，除了其他功能（包括关键自噬介体 Beclin-1 的激活）之外，还可以稳定核 p53。在正常生理条件下，Tp53 可以抑制自噬体的形成，但应激条件也会导致 Tp53 介导的自噬促进，表明 Tp53 的作用高度依赖于上下文。Tp53 靶基因在自噬诱导或抑制中也发挥关键的相反作用，例如 DRAM 和 TIGAR。最后，讨论了 Tp53 突变体在自噬调节中的作用。
