Complementary omics strategies to dissect p53 signaling networks under nutrient stress.

Carcinoma, Hepatocellular / metabolism Cell Nucleus / metabolism Cytoplasm / metabolism Humans Liver Neoplasms / metabolism Nutrients Signal Transduction / physiology Tumor Suppressor Protein p53 / genetics

Interactome Nutrient stress Starvation p53 signaling p53 targets

Journal

Cellular and molecular life sciences : CMLS

ISSN: 1420-9071

Titre abrégé: Cell Mol Life Sci

Pays: Switzerland

ID NLM: 9705402

Informations de publication

Date de publication:
30 May 2022

Historique:

received: 03 01 2022

accepted: 03 05 2022

revised: 21 04 2022

entrez: 31 5 2022

pubmed: 1 6 2022

medline: 3 6 2022

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1007/s00018-022-04345-8 PMID: 35635656 PMC: PMC9151573

pubmed: 35635656

doi: 10.1007/s00018-022-04345-8

pii: 10.1007/s00018-022-04345-8

pmc: PMC9151573

doi:

Substances chimiques

Tumor Suppressor Protein p53 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

326

Subventions

Organisme : Austrian Science Fund FWF

ID : DOC 31

Pays : Austria

Informations de copyright

Références

Levine AJ (2020) P53: 800 million years of evolution and 40 years of discovery. Nat Rev Cancer 20:471–480. https://doi.org/10.1038/s41568-020-0262-1

doi: 10.1038/s41568-020-0262-1 pubmed: 32404993

Kruse JP, Gu W (2009) Modes of p53 regulation. Cell 137:609–622. https://doi.org/10.1016/j.cell.2009.04.050

doi: 10.1016/j.cell.2009.04.050 pubmed: 19450511 pmcid: 3737742

Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137:413–431. https://doi.org/10.1016/j.cell.2009.04.037

doi: 10.1016/j.cell.2009.04.037 pubmed: 19410540

Kastenhuber ER, Lowe SW (2017) Putting p53 in context. Cell 170:1062–1078. https://doi.org/10.1016/j.cell.2017.08.028

doi: 10.1016/j.cell.2017.08.028 pubmed: 28886379 pmcid: 5743327

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013

doi: 10.1016/j.cell.2011.02.013 pubmed: 21376230

Levine AJ (2020) P53 and the immune response: 40 years of exploration—a plan for the future. Int J Mol Sci 21:541. https://doi.org/10.3390/ijms21020541

doi: 10.3390/ijms21020541 pmcid: 7013403

Lacroix M, Riscal R, Arena G et al (2020) Metabolic functions of the tumor suppressor p53: implications in normal physiology, metabolic disorders, and cancer. Mol Metab 33:2–22. https://doi.org/10.1016/j.molmet.2019.10.002

doi: 10.1016/j.molmet.2019.10.002 pubmed: 31685430

Simabuco FM, Morale MG, Pavan ICB et al (2018) P53 and metabolism: from mechanism to therapeutics. Oncotarget 9:23780–23823

doi: 10.18632/oncotarget.25267

Krstic J, Galhuber M, Schulz T et al (2018) p53 as a dichotomous regulator of liver disease: the dose makes the medicine. Int J Mol Sci 19:921. https://doi.org/10.3390/ijms19030921

doi: 10.3390/ijms19030921 pmcid: 5877782

Labuschagne CF, Zani F, Vousden KH (2018) BBA—reviews on cancer control of metabolism by p53—cancer and beyond ☆. BBA-Rev Cancer 1870:32–42. https://doi.org/10.1016/j.bbcan.2018.06.001

doi: 10.1016/j.bbcan.2018.06.001

Li M, Brooks CL, Wu-Baer F et al (2003) Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302:1972–1975. https://doi.org/10.1126/science.1091362

doi: 10.1126/science.1091362 pubmed: 14671306

Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420:25–27. https://doi.org/10.1016/S0014-5793(97)01480-4

doi: 10.1016/S0014-5793(97)01480-4 pubmed: 9450543

Gajjar M, Candeias MM, Malbert-Colas L et al (2012) The p53 mRNA-Mdm2 interaction controls mdm2 nuclear trafficking and is required for p53 activation following dna damage. Cancer Cell 21:25–35. https://doi.org/10.1016/j.ccr.2011.11.016

doi: 10.1016/j.ccr.2011.11.016 pubmed: 22264786

Candeias MM, Malbert-Colas L, Powell DJ et al (2008) p53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol 10:1098–1105. https://doi.org/10.1038/ncb1770

doi: 10.1038/ncb1770 pubmed: 19160491

Barak Y, Juven T, Haffner R, Oren M (1993) mdm2 expression is induced by wild type p53 activity. EMBO J 12:461–468. https://doi.org/10.1002/j.1460-2075.1993.tb05678.x

doi: 10.1002/j.1460-2075.1993.tb05678.x pubmed: 8440237 pmcid: 413229

Wu X, Bayle JH, Olson D, Levine AJ (1993) The p53-mdm-2 autoregulatory feedl ack loop. Genes Dev 53:1126–1132

doi: 10.1101/gad.7.7a.1126

Hock AK, Vousden KH (2014) The role of ubiquitin modification in the regulation of p53. Biochim Biophys Acta-Mol Cell Res 1843:137–149. https://doi.org/10.1016/j.bbamcr.2013.05.022

doi: 10.1016/j.bbamcr.2013.05.022

Liu Y, Tavana O, Gu W (2019) P53 modifications: exquisite decorations of the powerful guardian. J Mol Cell Biol 11:564–577. https://doi.org/10.1093/jmcb/mjz060

doi: 10.1093/jmcb/mjz060 pubmed: 31282934 pmcid: 6736412

Jiang P, Du W, Wang X et al (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13:310–316. https://doi.org/10.1038/ncb2172

doi: 10.1038/ncb2172 pubmed: 21336310 pmcid: 3110666

Fischer M (2017) Census and evaluation of p53 target genes. Oncogene 36:3943–3956. https://doi.org/10.1038/onc.2016.502

doi: 10.1038/onc.2016.502 pubmed: 28288132 pmcid: 5511239

Sullivan KD, Galbraith MD, Andrysik Z, Espinosa JM (2018) Mechanisms of transcriptional regulation by p53. Cell Death Differ 25:133–143. https://doi.org/10.1038/cdd.2017.174

doi: 10.1038/cdd.2017.174 pubmed: 29125602

Hafner A, Bulyk ML, Jambhekar A, Lahav G (2019) The multiple mechanisms that regulate p53 activity and cell fate. Nat Rev Mol Cell Biol. https://doi.org/10.1038/s41580-019-0110-x

doi: 10.1038/s41580-019-0110-x pubmed: 30824861

Nencioni A, Caffa I, Cortellino S, Longo VD (2018) Fasting and cancer: molecular mechanisms and clinical application. Nat Rev Cancer 18:707–719. https://doi.org/10.1038/s41568-018-0061-0

doi: 10.1038/s41568-018-0061-0 pubmed: 30327499 pmcid: 6938162

de Cabo R, Mattson MP (2019) Effects of intermittent fasting on health, aging, and disease. N Engl J Med 381:2541–2551. https://doi.org/10.1056/NEJMra1905136

doi: 10.1056/NEJMra1905136 pubmed: 31881139

Krstic J, Pieber TR, Prokesch A (2020) Stratifying nutritional restriction in cancer therapy: Next stop, personalized medicine. International Review of Cell and Molecular Biology. Elsevier Inc., Amsterdam, pp 231–259

Lévesque S, Le Naour J, Pietrocola F et al (2019) A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice. Oncoimmunology 8:e1657375. https://doi.org/10.1080/2162402X.2019.1657375

doi: 10.1080/2162402X.2019.1657375 pubmed: 31646107 pmcid: 6791453

Deligiorgi MV, Liapi C, Trafalis DT (2020) How far are we from prescribing fasting as anticancer medicine? Int J Mol Sci 21:9175. https://doi.org/10.3390/ijms21239175

doi: 10.3390/ijms21239175 pmcid: 7730661

Prokesch A, Graef FA, Madl T et al (2017) Liver p53 is stabilized upon starvation and required for amino acid catabolism and gluconeogenesis. FASEB J 31:732–742. https://doi.org/10.1096/fj.201600845R

doi: 10.1096/fj.201600845R pubmed: 27811061

Krstic J, Reinisch I, Schindlmaier K et al (2022) Fasting improves therapeutic response in hepatocellular carcinoma through p53-dependent metabolic synergism. Sci Adv. https://doi.org/10.1126/sciadv.abh2635

doi: 10.1126/sciadv.abh2635 pubmed: 35061544 pmcid: 8782451

Gonzalez-Rellan MJ, Fondevila MF, Fernandez U et al (2021) O-GlcNAcylated p53 in the liver modulates hepatic glucose production. Nat Commun 12:5068. https://doi.org/10.1038/s41467-021-25390-0

doi: 10.1038/s41467-021-25390-0 pubmed: 34417460 pmcid: 8379189

Wade M, Wang YV, Wahl GM (2010) The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol 20:299–309. https://doi.org/10.1016/j.tcb.2010.01.009

doi: 10.1016/j.tcb.2010.01.009 pubmed: 20172729 pmcid: 2910097

Lee JM, Wagner M, Xiao R et al (2014) Nutrient-sensing nuclear receptors coordinate autophagy. Nature 516:112–115. https://doi.org/10.1038/nature13961

doi: 10.1038/nature13961 pubmed: 25383539 pmcid: 4267857

Aubrey BJ, Kelly GL, Janic A et al (2018) How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ 25:104–113. https://doi.org/10.1038/cdd.2017.169

doi: 10.1038/cdd.2017.169 pubmed: 29149101

Vassilev LT, Vu BT, Graves B et al (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848. https://doi.org/10.1126/science.1092472

doi: 10.1126/science.1092472 pubmed: 14704432

O’Keefe K, Li H, Zhang Y (2003) Nucleocytoplasmic shuttling of p53 is essential for MDM2-mediated cytoplasmic degradation but not ubiquitination. Mol Cell Biol 23:6396–6405. https://doi.org/10.1128/MCB.23.18.6396-6405.2003

doi: 10.1128/MCB.23.18.6396-6405.2003 pubmed: 12944468 pmcid: 193719

Anwar A, Norris DA, Fujita M (2011) Ubiquitin proteasomal pathway mediated degradation of p53 in melanoma. Arch Biochem Biophys 508:198–203. https://doi.org/10.1016/j.abb.2010.12.012

doi: 10.1016/j.abb.2010.12.012 pubmed: 21167122

Branon TC, Bosch JA, Sanchez AD et al (2018) Efficient proximity labeling in living cells and organisms with TurboID. Nat Biotechnol. https://doi.org/10.1038/nbt.4201

doi: 10.1038/nbt.4201 pubmed: 30125270 pmcid: 6126969

Livesey KM, Kang R, Vernon P et al (2012) p53/HMGB1 complexes regulate autophagy and apoptosis. Cancer Res 72:1996–2005. https://doi.org/10.1158/0008-5472.CAN-11-2291

doi: 10.1158/0008-5472.CAN-11-2291 pubmed: 22345153 pmcid: 3417120

Ochocka AM, Kampanis P, Nicol S et al (2009) FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53. FEBS Lett 583:621–626. https://doi.org/10.1016/j.febslet.2009.01.009

doi: 10.1016/j.febslet.2009.01.009 pubmed: 19166840

Wang W, Wei J, Zhang H et al (2021) PRDX2 promotes the proliferation of colorectal cancer cells by increasing the ubiquitinated degradation of p53. Cell Death Dis 12:605. https://doi.org/10.1038/s41419-021-03888-1

doi: 10.1038/s41419-021-03888-1 pubmed: 34117220 pmcid: 8196203

Falcicchio M, Ward JA, Macip S, Doveston RG (2020) Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer. Cell death Discov 6:126. https://doi.org/10.1038/s41420-020-00362-3

doi: 10.1038/s41420-020-00362-3 pubmed: 33298896 pmcid: 7669891

Geeraerts SL, Heylen E, De Keersmaecker K, Kampen KR (2021) The ins and outs of serine and glycine metabolism in cancer. Nat Metab 3:131–141. https://doi.org/10.1038/s42255-020-00329-9

doi: 10.1038/s42255-020-00329-9 pubmed: 33510397

Ou Y, Wang SJ, Jiang L et al (2015) p53 Protein-mediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation. J Biol Chem 290:457–466. https://doi.org/10.1074/jbc.M114.616359

doi: 10.1074/jbc.M114.616359 pubmed: 25404730

DeBerardinis RJ, Chandel NS (2016) Fundamentals of cancer metabolism. Sci Adv 2:e1600200. https://doi.org/10.1126/sciadv.1600200

doi: 10.1126/sciadv.1600200 pubmed: 27386546 pmcid: 4928883

Saleem A, Hood DA (2013) Acute exercise induces tumour suppressor protein p53 translocation to the mitochondria and promotes a p53-Tfam-mitochondrial DNA complex in skeletal muscle. J Physiol 591:3625–3636. https://doi.org/10.1113/jphysiol.2013.252791

doi: 10.1113/jphysiol.2013.252791 pubmed: 23690562 pmcid: 3731618

Breitkreutz A, Choi H, Sharom JR et al (2010) A global protein kinase and phosphatase interaction network in yeast. Science 328:1043–1046. https://doi.org/10.1126/science.1176495

doi: 10.1126/science.1176495 pubmed: 20489023 pmcid: 3983991

Mellacheruvu D, Wright Z, Couzens AL et al (2013) The CRAPome: a contaminant repository for affinity purification-mass spectrometry data. Nat Methods 10:730–736. https://doi.org/10.1038/nmeth.2557

doi: 10.1038/nmeth.2557 pubmed: 23921808 pmcid: 3773500

Knight JDR, Liu G, Zhang JP et al (2015) A web-tool for visualizing quantitative protein-protein interaction data. Proteomics 15:1432–1436. https://doi.org/10.1002/pmic.201400429

doi: 10.1002/pmic.201400429 pubmed: 25422071

Flöter J, Kaymak I, Schulze A (2017) Regulation of metabolic activity by p53. Metabolites 7:21. https://doi.org/10.3390/metabo7020021

doi: 10.3390/metabo7020021 pmcid: 5487992

Bensaad K, Tsuruta A, Selak MA et al (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120. https://doi.org/10.1016/j.cell.2006.05.036

doi: 10.1016/j.cell.2006.05.036 pubmed: 16839880

Johnson DI (1999) Cdc42: an essential rho-type GTPase controlling eukaryotic cell polarity. Microbiol Mol Biol Rev 63:54–105. https://doi.org/10.1128/mmbr.63.1.54-105.1999

doi: 10.1128/mmbr.63.1.54-105.1999 pubmed: 10066831 pmcid: 98957

Stark C, Breitkreutz BJ, Reguly T et al (2006) BioGRID: a general repository for interaction datasets. Nucleic Acids Res 34:535–539. https://doi.org/10.1093/nar/gkj109

doi: 10.1093/nar/gkj109

Renkema GH, Pulkkinen K, Saksela K (2002) Cdc42/Rac1-mediated activation primes PAK2 for superactivation by tyrosine phosphorylation. Mol Cell Biol 22:6719–6725. https://doi.org/10.1128/mcb.22.19.6719-6725.2002

doi: 10.1128/mcb.22.19.6719-6725.2002 pubmed: 12215529 pmcid: 134024

Madeira F, Tinti M, Murugesan G et al (2015) 14-3-3-Pred: improved methods to predict 14-3-3-binding phosphopeptides. Bioinformatics 31:2276–2283. https://doi.org/10.1093/bioinformatics/btv133

doi: 10.1093/bioinformatics/btv133 pubmed: 25735772 pmcid: 4495292

Yeo D, He H, Patel O et al (2016) FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine. BMC Cancer 16:24. https://doi.org/10.1186/s12885-016-2057-z

doi: 10.1186/s12885-016-2057-z pubmed: 26774265 pmcid: 4715347

Cai Q, Xiao B, Si H et al (2012) Kaposi’s sarcoma herpesvirus upregulates Aurora A expression to promote p53 phosphorylation and ubiquitylation. PLoS Pathog 8:e1002566. https://doi.org/10.1371/journal.ppat.1002566

doi: 10.1371/journal.ppat.1002566 pubmed: 22396649 pmcid: 3291660

Mohammed H, Taylor C, Brown GD et al (2016) Rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) for analysis of chromatin complexes. Nat Protoc 11:316–326. https://doi.org/10.1038/nprot.2016.020

doi: 10.1038/nprot.2016.020 pubmed: 26797456

Choi H, Larsen B, Lin ZY et al (2011) SAINT: probabilistic scoring of affinity purificationg-mass spectrometry data. Nat Methods 8:70–73. https://doi.org/10.1038/nmeth.1541

doi: 10.1038/nmeth.1541 pubmed: 21131968

Bharucha DC, Zhou M, Nekhai S et al (2002) A protein phosphatase from human T cells augments tat transactivation of the human immunodeficiency virus type 1 long-terminal repeat. Virology 296:6–16. https://doi.org/10.1006/viro.2002.1438

doi: 10.1006/viro.2002.1438 pubmed: 12036313

Schupp M, Chen F, Briggs ER et al (2013) Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues. BMC Genomics 14:758. https://doi.org/10.1186/1471-2164-14-758

doi: 10.1186/1471-2164-14-758 pubmed: 24191950 pmcid: 3907060

Zhang QC, Petrey D, Garzón JI et al (2013) PrePPI: a structure-informed database of protein-protein interactions. Nucleic Acids Res 41:828–833. https://doi.org/10.1093/nar/gks1231

doi: 10.1093/nar/gks1231

Zhang QC, Petrey D, Deng L et al (2012) Structure-based prediction of protein-protein interactions on a genome-wide scale. Nature 490:556–560. https://doi.org/10.1038/nature11503

doi: 10.1038/nature11503 pubmed: 23023127 pmcid: 3482288

Baumann CA, Ribon V, Kanzaki M et al (2000) CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 407:202–207. https://doi.org/10.1038/35025089

doi: 10.1038/35025089 pubmed: 11001060

Jones RG, Plas DR, Kubek S et al (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283–293. https://doi.org/10.1016/j.molcel.2005.03.027

doi: 10.1016/j.molcel.2005.03.027 pubmed: 15866171

Labuschagne CF, Zani F, Vousden KH (2018) Control of metabolism by p53-cancer and beyond. Biochim Biophys Acta 56:1511–1519. https://doi.org/10.1016/j.bbcan.2018.06.001

doi: 10.1016/j.bbcan.2018.06.001

Mhawech P (2005) 14–3-3 proteins—an update. Cell Res 15:228–236. https://doi.org/10.1038/sj.cr.7290291

doi: 10.1038/sj.cr.7290291 pubmed: 15857577

Livesey KM, Kang R, Zeh HJ et al (2012) Direct molecular interactions between HMGB1 and TP53 in colorectal cancer. Autophagy 8:846–848. https://doi.org/10.4161/auto.19891

doi: 10.4161/auto.19891 pubmed: 22647615 pmcid: 3378423

Štros M, Muselikova-Polanska E, Pospisilova S, Strauss F (2004) High-affinity binding of tumor-suppressor protein p53 and HMGB1 to hemicatenated DNA loops. Biochemistry 43:7215–7225. https://doi.org/10.1021/bi049928k

doi: 10.1021/bi049928k pubmed: 15170359

Rowell JP, Simpson KL, Stott K et al (2012) HMGB1-facilitated p53 DNA binding occurs via HMG-Box/p53 transactivation domain interaction, regulated by the acidic tail. Structure 20:2014–2024. https://doi.org/10.1016/j.str.2012.09.004

doi: 10.1016/j.str.2012.09.004 pubmed: 23063560

Jing X, Wang XJ, Zhang T et al (2019) Cell-cycle-dependent phosphorylation of PrPS1 fuels nucleotide synthesis and promotes tumorigenesis. Cancer Res 79:4650–4664. https://doi.org/10.1158/0008-5472.CAN-18-2486

doi: 10.1158/0008-5472.CAN-18-2486 pubmed: 31253668

Ge T, Yang J, Zhou S et al (2020) The role of the pentose phosphate pathway in diabetes and cancer. Front Endocrinol (Lausanne) 11:365. https://doi.org/10.3389/fendo.2020.00365

doi: 10.3389/fendo.2020.00365

Hardie DG (2015) AMPK: Positive and negative regulation, and its role in whole-body energy homeostasis. Curr Opin Cell Biol 33:1–7. https://doi.org/10.1016/j.ceb.2014.09.004

doi: 10.1016/j.ceb.2014.09.004 pubmed: 25259783

Banko MR, Allen JJ, Schaffer BE et al (2011) Chemical genetic screen for AMPKα2 substrates uncovers a network of proteins involved in mitosis. Mol Cell 44:878–892. https://doi.org/10.1016/j.molcel.2011.11.005

doi: 10.1016/j.molcel.2011.11.005 pubmed: 22137581 pmcid: 3246132

Yeh PY, Chuang SE, Yeh KH et al (2004) Phosphorylation of p53 on Thr55 by ERK2 is necessary for doxorubicin-induced p53 activation and cell death. Oncogene 23:3580–3588. https://doi.org/10.1038/sj.onc.1207426

doi: 10.1038/sj.onc.1207426 pubmed: 15116093

Sablina AA, Chumakov PM, Levine AJ, Kopnin BP (2001) p53 activation in response to microtubule disruption is mediated by integrin-Erk signaling. Oncogene 20:899–909. https://doi.org/10.1038/sj.onc.1204156

doi: 10.1038/sj.onc.1204156 pubmed: 11314025

Heyen CA, Tagliabracci VS, Zhai L, Roach PJ (2009) Characterization of mouse UDP-glucose pyrophosphatase, a Nudix hydrolase encoded by the Nudt14 gene. Biochem Biophys Res Commun 390:1414–1418. https://doi.org/10.1016/j.bbrc.2009.11.007

doi: 10.1016/j.bbrc.2009.11.007 pubmed: 19896456 pmcid: 2798163

Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS (2012) Glycogen and its metabolism: some new developments and old themes. Biochem J 441:763–787. https://doi.org/10.1042/BJ20111416

doi: 10.1042/BJ20111416 pubmed: 22248338

Sun RC, Dukhande VV, Zhou Z et al (2019) Nuclear glycogenolysis modulates histone acetylation in human non-small cell lung cancers. Cell Metab 30:903-916.e7. https://doi.org/10.1016/j.cmet.2019.08.014

doi: 10.1016/j.cmet.2019.08.014 pubmed: 31523006 pmcid: 6834909

Hancock ML, Meyer RC, Mistry M et al (2019) Insulin receptor associates with promoters genome-wide and regulates gene expression. Cell 177:722-736.e22. https://doi.org/10.1016/j.cell.2019.02.030

doi: 10.1016/j.cell.2019.02.030 pubmed: 30955890 pmcid: 6478446

Liao Y, Wang J, Jaehnig EJ et al (2019) WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res 47:W199–W205. https://doi.org/10.1093/nar/gkz401

doi: 10.1093/nar/gkz401 pubmed: 31114916 pmcid: 6602449

Cox J, Hein MY, Luber CA, Paron I, Nagaraj N, Mann M (2014) Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ. Mol Cell Proteomics 13(9):2513–2526. https://doi.org/10.1074/mcp.M113.031591

doi: 10.1074/mcp.M113.031591 pubmed: 24942700 pmcid: 4159666

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29(1):15–21. https://doi.org/10.1093/bioinformatics/bts635

doi: 10.1093/bioinformatics/bts635 pubmed: 23104886

Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38(4):576–89. https://doi.org/10.1016/j.molcel.2010.05.004

doi: 10.1016/j.molcel.2010.05.004 pubmed: 20513432 pmcid: 2898526

Daily K, Patel VR, Rigor P, Xie X, Baldi P (2011) MotifMap: integrative genome-wide maps of regulatory motif sites for model species. BMC Bioinformatics 12:495. https://doi.org/10.1186/1471-2105-12-495

doi: 10.1186/1471-2105-12-495 pubmed: 22208852 pmcid: 3293935

Wickham H (2016) Ggplot2. Elegant graphics for data analysis, Springer, New York

doi: 10.1007/978-3-319-24277-4