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Complementary Omics Strategies to Dissect p53 Signaling Networks Under Nutrient Stress

54 Pages Posted: 21 Sep 2021 Publication Status: Review Complete

See all articles by Markus Galhuber

Markus Galhuber

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

Helene Michenthaler

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

Christoph Heininger

affiliation not provided to SSRN

Isabel Reinisch

affiliation not provided to SSRN

Christoph Nössing

Cancer Research UK Beatson Institute

Jelena Krstic

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

Nadja Kupper

affiliation not provided to SSRN

Elisabeth Moyschewitz

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

Martina Auer

affiliation not provided to SSRN

Ellen Heitzer

Medical University of Graz - Institute of Human Genetics

Peter Ulz

affiliation not provided to SSRN

Ruth Birner-Gruenberger

affiliation not provided to SSRN

Laura Liesinger

affiliation not provided to SSRN

Georgia Ngawai Lenihan-Geels

affiliation not provided to SSRN

Moritz Oster

affiliation not provided to SSRN

Emil Spreitzer

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry

Riccardo Zenezini Chiozzi

affiliation not provided to SSRN

Tim Julius Schulz

German Institute of Human Nutrition - Department of Adipocyte Development and Nutrition

Michael Schupp

Charité - Universitätsmedizin Berlin - Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research

Tobias Madl

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

Albert J.R. Heck

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group

Andreas Prokesch

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

More...

Abstract

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.

Keywords: p53 signaling, Nutrient Stress, starvation, Interactome, p53 targets

Suggested Citation

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.

Markus Galhuber

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

Helene Michenthaler

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

Christoph Heininger

affiliation not provided to SSRN

No Address Available

Isabel Reinisch

affiliation not provided to SSRN

No Address Available

Christoph Nössing

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Jelena Krstic

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

Nadja Kupper

affiliation not provided to SSRN

No Address Available

Elisabeth Moyschewitz

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

Martina Auer

affiliation not provided to SSRN

No Address Available

Ellen Heitzer

Medical University of Graz - Institute of Human Genetics ( email )

Austria

Peter Ulz

affiliation not provided to SSRN

No Address Available

Ruth Birner-Gruenberger

affiliation not provided to SSRN

No Address Available

Laura Liesinger

affiliation not provided to SSRN

No Address Available

Georgia Ngawai Lenihan-Geels

affiliation not provided to SSRN

No Address Available

Moritz Oster

affiliation not provided to SSRN

No Address Available

Emil Spreitzer

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry

Auenbruggerpl. 2
Graz, 8036
Austria

Riccardo Zenezini Chiozzi

affiliation not provided to SSRN

No Address Available

Tim Julius Schulz

German Institute of Human Nutrition - Department of Adipocyte Development and Nutrition

Michael Schupp

Charité - Universitätsmedizin Berlin - Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research

Tobias Madl

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging ( email )

Austria

Albert J.R. Heck

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group ( email )

Padualaan 8,
Utrecht, 3584 CH
Netherlands

Andreas Prokesch (Contact Author)

Medical University of Graz - Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging

Austria

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