Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, 8010, Graz, Austria.
Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK.
Cell Mol Life Sci. 2022 May 30;79(6):326. doi: 10.1007/s00018-022-04345-8.
Signaling trough p53is a major cellular stress response mechanism and increases upon nutrient stresses such as starvation. Here, we show in a human hepatoma cell line that starvation leads to robust nuclear p53 stabilization. Using BioID, we determine the cytoplasmic p53 interaction network within the immediate-early starvation response and show that p53 is dissociated from several metabolic enzymes and the kinase PAK2 for which direct binding with the p53 DNA-binding domain was confirmed with NMR studies. Furthermore, proteomics after p53 immunoprecipitation (RIME) uncovered the nuclear interactome under prolonged starvation, where we confirmed the novel p53 interactors SORBS1 (insulin receptor signaling) and UGP2 (glycogen synthesis). Finally, transcriptomics after p53 re-expression revealed a distinct starvation-specific transcriptome response and suggested previously unknown nutrient-dependent p53 target genes. Together, our complementary approaches delineate several nodes of the p53 signaling cascade upon starvation, shedding new light on the mechanisms of p53 as nutrient stress sensor. Given the central role of p53 in cancer biology and the beneficial effects of fasting in cancer treatment, the identified interaction partners and networks could pinpoint novel pharmacologic targets to fine-tune p53 activity.
p53 信号通路是细胞应激反应的主要机制之一，在营养应激（如饥饿）时会增加。在这里，我们在人肝癌细胞系中表明，饥饿会导致核 p53 稳定。通过 BioID，我们确定了即时早期饥饿反应中的细胞质 p53 相互作用网络，并表明 p53 与几种代谢酶和激酶 PAK2 分离，后者与 p53 DNA 结合域的直接结合已通过 NMR 研究得到证实。此外，p53 免疫沉淀（RIME）后的蛋白质组学揭示了长时间饥饿下的核相互作用组，我们在其中确认了 SORBS1（胰岛素受体信号）和 UGP2（糖原合成）这两个新的 p53 相互作用蛋白。最后，p53 重新表达后的转录组学揭示了一个独特的饥饿特异性转录组反应，并提出了以前未知的依赖营养的 p53 靶基因。总的来说，我们的互补方法描绘了饥饿时 p53 信号级联中的几个节点，为 p53 作为营养应激传感器的机制提供了新的见解。鉴于 p53 在癌症生物学中的核心作用以及禁食在癌症治疗中的有益效果，所鉴定的相互作用伙伴和网络可能会确定新的药物靶点，以微调 p53 活性。
