Markus Galhuber, Helene Michenthaler, Christoph Heininger, Isabel Reinisch, Christoph Nössing, Jelena Krstic, Nadja Kupper, Elisabeth Moyschewitz, Martina Auer, Ellen Heitzer, Peter Ulz, Ruth Birner-Gruenberger, Laura Liesinger, Georgia Ngawai Lenihan-Geels, Moritz Oster, Emil Spreitzer, Riccardo Zenezini Chiozzi, Tim J. Schulz, Michael Schupp, Tobias Madl, Albert J. R. Heck, Andreas Prokesch
- 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 newSignaling 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.…
MetadatenAuthor details: | Markus Galhuber, Helene Michenthaler, Christoph Heininger, Isabel Reinisch, Christoph Nössing, Jelena KrsticORCiD, Nadja Kupper, Elisabeth Moyschewitz, Martina Auer, Ellen Heitzer, Peter Ulz, Ruth Birner-Gruenberger, Laura Liesinger, Georgia Ngawai Lenihan-GeelsORCiD, Moritz Oster, Emil Spreitzer, Riccardo Zenezini Chiozzi, Tim J. SchulzORCiDGND, Michael Schupp, Tobias Madl, Albert J. R. Heck, Andreas Prokesch |
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DOI: | https://doi.org/10.1007/s00018-022-04345-8 |
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ISSN: | 1420-682X |
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ISSN: | 1420-9071 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/35635656 |
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Title of parent work (English): | Cellular and molecular life sciences |
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Publisher: | Springer Nature |
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Place of publishing: | Basel |
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Publication type: | Article |
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Language: | English |
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Date of first publication: | 2022/05/30 |
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Publication year: | 2022 |
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Release date: | 2024/07/01 |
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Tag: | Interactome; Nutrient stress; Starvation; p53 signaling; p53 targets |
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Volume: | 79 |
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Issue: | 6 |
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Article number: | 326 |
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Number of pages: | 22 |
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Funding institution: | Medical University of Graz; Austrian Science Fund (FWF) [P29328, I3165,; P34109, KLI645]; MEFOgraz grant from the Medical University of Graz;; EPIC-XS project - Horizon 2020 program of the European Union; [EPIC-XS-0000206]; PhD faculty MolMed at the Medical University of Graz;; Oesterreichische Nationalbank (Austrian Central Bank, Anniversary Fund); [18517]; MEFOgraz research grant; German Research foundation [SCHU; 2546/4-1]; Doctoral school "DK Metabolic and Cardiovascular disease"; [W1226]; SFB "Lipid hydrolysis" (F73) |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
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Peer review: | Referiert |
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Publishing method: | Open Access / Hybrid Open-Access |
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License (German): | CC-BY - Namensnennung 4.0 International |
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