Signaling trough p53 is 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.
Galhuber, Markus and Michenthaler, Helene and Heininger, Christoph and Reinisch, Isabel and Nössing, Christoph and Krstic, Jelena and Kupper, Nadja and Moyschewitz, Elisabeth and Auer, Martina and Heitzer, Ellen and Ulz, Peter and Birner-Gruenberger, Ruth and Liesinger, Laura and Lenihan-Geels, Georgia Ngawai and Oster, Moritz and Spreitzer, Emil and Zenezini Chiozzi, Riccardo and Schulz, Tim Julius and Schupp, Michael and Madl, Tobias and Heck, Albert J.R. and Prokesch, Andreas, Complementary Omics Strategies to Dissect p53 Signaling Networks Under Nutrient Stress. Available at SSRN: https://ssrn.com/abstract=3928086 or http://dx.doi.org/10.2139/ssrn.3928086
This version of the paper has not been formally peer reviewed.