Complementary omics strategies to dissect p53 signaling networks under nutrient stress

Author:

Galhuber Markus,Michenthaler Helene,Heininger Christoph,Reinisch Isabel,Nössing Christoph,Krstic Jelena,Kupper Nadja,Moyschewitz Elisabeth,Auer Martina,Heitzer Ellen,Ulz Peter,Birner-Gruenberger Ruth,Liesinger Laura,Lenihan-Geels Georgia Ngawai,Oster Moritz,Spreitzer Emil,Zenezini Chiozzi Riccardo,Schulz Tim J.,Schupp Michael,Madl Tobias,Heck Albert J. R.,Prokesch AndreasORCID

Abstract

AbstractSignaling 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.

Funder

Austrian Science Fund

Horizon 2020 Framework Programme

Oesterreichische Nationalbank

Deutsche Forschungsgemeinschaft

Medical University of Graz

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Cellular and Molecular Neuroscience,Pharmacology,Molecular Biology,Molecular Medicine

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