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The Role of Tumor Suppressor p53 in the Antioxidant Defense and Metabolism

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Mutant p53 and MDM2 in Cancer

Part of the book series: Subcellular Biochemistry ((SCBI,volume 85))

Abstract

Tumor suppressor p53 is inactivated in most cancers and the critical role of p53 in the suppression of carcinogenesis has been confirmed in many mouse models. The protein product of the tumor suppressor p53 gene works as a transcriptional regulator, activating expression of numerous genes involved in cell death, cell cycle arrest, senescence, DNA-repair and many other processes. In spite of the multiple efforts to characterize the functions of p53, the mechanisms of tumor suppression by p53 are still elusive. Recently, new activities of p53 such as regulation of reactive oxygen species (ROS) and metabolism have been described and the p53-regulated genes responsible for these functions have been identified. Metabolic derangements and accumulation of ROS are features of carcinogenesis, supporting the idea that many tumor suppressive effects of p53 can be mediated by regulation of metabolism and/or ROS. Mutations in the p53 gene can not only inactivate wild type function of p53 but also endow p53 with new functions such as activation of new metabolic pathways contributing to carcinogenesis. Understanding the metabolic and antioxidant functions of p53 allows us to develop approaches to restore p53 function in cancers, where p53 is inactivated, in other to ensure the best outcome of anti-cancer treatment.

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Abbreviations

4EBP1:

eIF-4E binding protein 1

Atg1-17:

autophagy gene 1–17

AIF:

apoptosis-inducing factor

AMPK:

AMP activated protein kinase

Arf1:

alternative reading frame 1

ATP:

adenosine triphosphate

ATM:

ataxia-telangiectasia mutated kinase

ATR:

ATM related kinase

Chk1/Chk2:

checkpoint kinase 1/2

COP1:

constitutively photomorphogenic 1

eIF-4E:

eukaryotic translation initiation factor 4E

FPP:

farnesyl pyrophosphate

FoxO:

forkhead box O transcription factors

GAMT:

guanidinoacetate methyltransferase

GGPP:

geranylgeranyl pyrophosphate

GLS2:

glutaminase 2

GPX1:

glutathione peroxidase 1

GSH:

glutathione

GSSG:

oxidized form of glutathione

HIF1:

hypoxia-inducible factor 1

HK2:

mitochondrial hexokinase 2

Keap1:

Kelch-like ECH-associated protein 1

MnSOD:

manganese superoxide dismutase

Mdm2:

mouse double minute

NAC:

N-acetyl cysteine

NCF2/p67phox:

neutrophil cytosol factor 2

NRF2:

nuclear factor (erythroid-derived 2)-like 2

mTOR:

mammalian target of rapamycin kinase

mTORC1/2:

mTOR complex 1/2

p53INP1:

p53-inducible nuclear protein 1

PET:

paired-end ditag

PGC1α:

PPARγ coactivator 1α

PGM:

phosphoglycerate mutase

PFK-2/FBPase-2:

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase

PIG1-13:

p53-inducible genes 1–13

PIRH2:

p53-induced protein with a RING (Really Interesting New Gene)-H2 domain

PPARα/γ:

peroxisome proliferator-activated receptor α/γ

RagA,B,C,D:

Ras-related GTP-binding protein A,B,C,D

Rheb:

Ras homolog enriched in brain

ROS:

reactive oxygen species

SCO2:

synthesis of cytochrome C oxidase 2

SREBP1:

sterol-regulatory element binding protein 1

TAp73:

transcriptionally active p73

TIGAR:

p53-induced glycolysis and apoptotic regulator

TSC1/2:

tuberoses sclerosis complex protein 1/2

References

  1. Achanta G, Sasaki R, Feng L, Carew JS, Lu W, Pelicano H, Keating MJ, Huang P (2005) Novel role of p53 in maintaining mitochondrial genetic stability through interaction with DNA Pol gamma. EMBO J 24:3482–3492

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Assaily W, Rubinger DA, Wheaton K, Lin Y, Ma W, Xuan W, Brown-Endres L, Tsuchihara K, Mak TW, Benchimol S (2011) ROS-mediated p53 induction of Lpin1 regulates fatty acid oxidation in response to nutritional stress. Mol Cell 44:491–501

    CAS  PubMed  Google Scholar 

  3. Bae SH, Sung SH, Oh SY, Lim JM, Lee SK, Park YN, Lee HE, Kang D, Rhee SG (2013) Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab 17:73–84

    CAS  PubMed  Google Scholar 

  4. Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495

    CAS  PubMed  Google Scholar 

  5. Behrend L, Henderson G, Zwacka RM (2003) Reactive oxygen species in oncogenic transformation. Biochem Soc Trans 31:1441–1444

    CAS  PubMed  Google Scholar 

  6. Ben-Sahra I, Dirat B, Laurent K, Puissant A, Auberger P, Budanov A, Tanti JF, Bost F (2013) Sestrin2 integrates Akt and mTOR signaling to protect cells against energetic stress-induced death. Cell Death Differ 20:611–619

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Ben-Sahra I, Howell JJ, Asara JM, Manning BD (2013) Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339:1323–1328

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120

    CAS  PubMed  Google Scholar 

  9. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591–602

    CAS  PubMed  Google Scholar 

  10. Bond GL, Hu W, Levine AJ (2005) MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets 5:3–8

    CAS  PubMed  Google Scholar 

  11. Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C (2002) Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science 295:1073–1077

    CAS  PubMed  Google Scholar 

  12. Budanov AV (2011) Stress-responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling. Antioxid Redox Signal 15:1679–1690

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Budanov AV, Karin M (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134:451–460

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Budanov AV, Lee JH, Karin M (2010) Stressin’ Sestrins take an aging fight. EMBO Mol Med 2:388–400

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Budanov AV, Sablina AA, Feinstein E, Koonin EV, Chumakov PM (2004) Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304:596–600

    CAS  PubMed  Google Scholar 

  16. Budanov AV, Shoshani T, Faerman A, Zelin E, Kamer I, Kalinski H, Gorodin S, Fishman A, Chajut A, Einat P et al (2002) Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene 21:6017–6031

    CAS  PubMed  Google Scholar 

  17. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67:6745–6752

    CAS  PubMed  Google Scholar 

  18. Cano CE, Gommeaux J, Pietri S, Culcasi M, Garcia S, Seux M, Barelier S, Vasseur S, Spoto RP, Pebusque MJ et al (2009) Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function. Cancer Res 69:219–226

    CAS  PubMed  Google Scholar 

  19. Cheung EC, Ludwig RL, Vousden KH (2012) Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc Natl Acad Sci U S A 109:20491–20496

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Cooks T, Pateras IS, Tarcic O, Solomon H, Schetter AJ, Wilder S, Lozano G, Pikarsky E, Forshew T, Rozenfeld N et al (2013) Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell 23:634–646

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM (2006) DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126:121–134

    CAS  PubMed  Google Scholar 

  22. Cui X (2012) Reactive oxygen species: the achilles’ heel of cancer cells? Antioxid Redox Signal 16:1212–1214

    CAS  PubMed Central  PubMed  Google Scholar 

  23. D’Autreaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8:813–824

    PubMed  Google Scholar 

  24. DeBerardinis RJ, Thompson CB (2012) Cellular metabolism and disease: what do metabolic outliers teach us? Cell 148:1132–1144

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P (1995) Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82:675–684

    CAS  PubMed  Google Scholar 

  26. Di Como CJ, Gaiddon C, Prives C (1999) p73 function is inhibited by tumor-derived p53 mutants in mammalian cells. Mol Cell Biol 19:1438–1449

    PubMed Central  PubMed  Google Scholar 

  27. Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–221

    CAS  PubMed  Google Scholar 

  28. Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P, O'Rourke K, Koeppen H, Dixit VM (2004) The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 429:86–92

    CAS  PubMed  Google Scholar 

  29. Essler S, Dehne N, Brune B (2009) Role of sestrin2 in peroxide signaling in macrophages. FEBS Lett 583:3531–3535

    CAS  PubMed  Google Scholar 

  30. Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci U S A 102:8204–8209

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247

    CAS  PubMed  Google Scholar 

  32. Freed-Pastor WA, Mizuno H, Zhao X, Langerod A, Moon SH, Rodriguez-Barrueco R, Barsotti A, Chicas A, Li W, Polotskaia A et al (2012) Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148:244–258

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Freed-Pastor WA, Prives C (2012) Mutant p53: one name, many proteins. Genes Dev 26:1268–1286

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Gao W, Shen Z, Shang L, Wang X (2011) Upregulation of human autophagy-initiation kinase ULK1 by tumor suppressor p53 contributes to DNA-damage-induced cell death. Cell Death Differ 18:1598–1607

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Green DR, Kroemer G (2009) Cytoplasmic functions of the tumour suppressor p53. Nature 458:1127–1130

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Hagenbuchner J, Kuznetsov A, Hermann M, Hausott B, Obexer P, Ausserlechner MJ (2012) FOXO3-induced reactive oxygen species are regulated by BCL2L11 (Bim) and SESN3. J Cell Sci 125(Pt 5):1191–1203

    CAS  PubMed  Google Scholar 

  37. Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420:25–27

    CAS  PubMed  Google Scholar 

  38. Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z (2010) Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci U S A 107:7455–7460

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Hussain SP, Amstad P, He P, Robles A, Lupold S, Kaneko I, Ichimiya M, Sengupta S, Mechanic L, Okamura S et al (2004) p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. Cancer Res 64:2350–2356

    CAS  PubMed  Google Scholar 

  40. Ide T, Brown-Endres L, Chu K, Ongusaha PP, Ohtsuka T, El-Deiry WS, Aaronson SA, Lee SW (2009) GAMT, a p53-inducible modulator of apoptosis, is critical for the adaptive response to nutrient stress. Mol Cell 36:379–392

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Italiano D, Lena AM, Melino G, Candi E (2012) Identification of NCF2/p67phox as a novel p53 target gene. Cell Cycle 11:4589–4596

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Jeffers JR, Parganas E, Lee Y, Yang C, Wang J, Brennan J, MacLean KH, Han J, Chittenden T, Ihle JN et al (2003) Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4:321–328

    CAS  PubMed  Google Scholar 

  43. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283–293

    CAS  PubMed  Google Scholar 

  44. Jones SN, Roe AE, Donehower LA, Bradley A (1995) Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378:206–208

    CAS  PubMed  Google Scholar 

  45. Kalo E, Kogan-Sakin I, Solomon H, Bar-Nathan E, Shay M, Shetzer Y, Dekel E, Goldfinger N, Buganim Y, Stambolsky P et al (2012) Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species. J Cell Sci 125:5578–5586

    CAS  PubMed  Google Scholar 

  46. Kang MY, Kim HB, Piao C, Lee KH, Hyun JW, Chang IY, You HJ (2013) The critical role of catalase in prooxidant and antioxidant function of p53. Cell Death Differ 20:117–129

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Kenzelmann Broz D, Spano Mello S, Bieging KT, Jiang D, Dusek RL, Brady CA, Sidow A, Attardi LD (2013) Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. Genes Dev 27:1016–1031

    PubMed Central  PubMed  Google Scholar 

  48. Kitamura N, Nakamura Y, Miyamoto Y, Miyamoto T, Kabu K, Yoshida M, Futamura M, Ichinose S, Arakawa H (2011) Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. PLoS One 6:e16060

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Kopnin PB, Agapova LS, Kopnin BP, Chumakov PM (2007) Repression of sestrin family genes contributes to oncogenic Ras-induced reactive oxygen species up-regulation and genetic instability. Cancer Res 67:4671–4678

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40:280–293

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Lahav G, Rosenfeld N, Sigal A, Geva-Zatorsky N, Levine AJ, Elowitz MB, Alon U (2004) Dynamics of the p53-Mdm2 feedback loop in individual cells. Nat Genet 36:147–150

    CAS  PubMed  Google Scholar 

  52. Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358:15–16

    CAS  PubMed  Google Scholar 

  53. Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM, Valentin-Vega YA, Terzian T, Caldwell LC, Strong LC et al (2004) Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119:861–872

    CAS  PubMed  Google Scholar 

  54. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Lebedeva MA, Eaton JS, Shadel GS (2009) Loss of p53 causes mitochondrial DNA depletion and altered mitochondrial reactive oxygen species homeostasis. Biochim Biophys Acta 1787:328–334

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Lee H, Cho JS, Lambacher N, Lee J, Lee SJ, Lee TH, Gartner A, Koo HS (2008) The Caenorhabditis elegans AMP-activated protein kinase AAK-2 is phosphorylated by LKB1 and is required for resistance to oxidative stress and for normal motility and foraging behavior. J Biol Chem 283:14988–14993

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, Ocorr K, Ellisman MH, Bodmer R, Bier E et al (2009) Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327:1223–1228

    Google Scholar 

  58. Lee JH, Budanov AV, Talukdar S, Park EJ, Park HL, Park HW, Bandyopadhyay G, Li N, Aghajan M, Jang I et al (2012) Maintenance of metabolic homeostasis by sestrin2 and sestrin3. Cell Metab 16:311–321

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Lee SO, Andey T, Jin UH, Kim K, Sachdeva M, Safe S (2011) The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53. Oncogene 31(27):3265–3276

    PubMed Central  PubMed  Google Scholar 

  60. Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S (2003) Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 112:779–791

    CAS  PubMed  Google Scholar 

  61. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331

    CAS  PubMed  Google Scholar 

  62. Levine AJ, Feng Z, Mak TW, You H, Jin S (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20:267–275

    CAS  PubMed  Google Scholar 

  63. Li FP, Fraumeni JF Jr (1969) Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 43:1365–1373

    CAS  PubMed  Google Scholar 

  64. Li FP, Fraumeni JF Jr (1969) Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71:747–752

    CAS  PubMed  Google Scholar 

  65. Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y, Baer R, Gu W (2012) Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149:1269–1283

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Liang Y, Liu J, Feng Z (2013) The regulation of cellular metabolism by tumor suppressor p53. Cell Biosci 3:9

    PubMed Central  PubMed  Google Scholar 

  67. Loayza-Puch F, Drost J, Rooijers K, Lopes R, Elkon R, Agami R (2013) p53 induces transcriptional and translational programs to suppress cell proliferation and growth. Genome Biol 14:R32

    PubMed Central  PubMed  Google Scholar 

  68. Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, Vousden KH (2013) Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493:542–546

    CAS  PubMed  Google Scholar 

  69. Maddocks OD, Vousden KH (2011) Metabolic regulation by p53. J Mol Med (Berl) 89:237–245

    CAS  Google Scholar 

  70. Maiuri MC, Malik SA, Morselli E, Kepp O, Criollo A, Mouchel PL, Carnuccio R, Kroemer G (2009) Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle 8:1571–1576

    CAS  PubMed  Google Scholar 

  71. Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192:1–15

    CAS  PubMed  Google Scholar 

  72. Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, Flores JM, Vina J, Blasco MA, Serrano M (2007) Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448:375–379

    CAS  PubMed  Google Scholar 

  73. Mathew R, Karantza-Wadsworth V, White E (2007) Role of autophagy in cancer. Nat Rev Cancer 7:961–967

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM (2006) p53 regulates mitochondrial respiration. Science 312:1650–1653

    CAS  PubMed  Google Scholar 

  75. Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Morselli E, Shen S, Ruckenstuhl C, Bauer MA, Marino G, Galluzzi L, Criollo A, Michaud M, Maiuri MC, Chano T et al (2011) p53 inhibits autophagy by interacting with the human ortholog of yeast Atg17, RB1CC1/FIP200. Cell Cycle 10:2763–2769

    CAS  PubMed  Google Scholar 

  77. Muller PA, Vousden KH (2013) p53 mutations in cancer. Nat Cell Biol 15:2–8

    CAS  PubMed  Google Scholar 

  78. N’Guessan P, Pouyet L, Gosset G, Hamlaoui S, Seillier M, Cano CE, Seux M, Stocker P, Culcasi M, Iovanna JL et al (2011) Absence of tumor suppressor tumor protein 53-induced nuclear protein 1 (TP53INP1) sensitizes mouse thymocytes and embryonic fibroblasts to redox-driven apoptosis. Antioxid Redox Signal 15:1639–1653

    PubMed  Google Scholar 

  79. Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, Unterman T, Hay N (2008) Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14:458–470

    CAS  PubMed Central  PubMed  Google Scholar 

  80. O’Connor JC, Wallace DM, O’Brien CJ, Cotter TG (2008) A novel antioxidant function for the tumor-suppressor gene p53 in the retinal ganglion cell. Invest Ophthalmol Vis Sci 49:4237–4244

    PubMed  Google Scholar 

  81. Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, Crowley D, Jacks T (2004) Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119:847–860

    CAS  PubMed  Google Scholar 

  82. Papadia S, Soriano FX, Leveille F, Martel MA, Dakin KA, Hansen HH, Kaindl A, Sifringer M, Fowler J, Stefovska V et al (2008) Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci 11:476–487

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Peeters H, Debeer P, Bairoch A, Wilquet V, Huysmans C, Parthoens E, Fryns JP, Gewillig M, Nakamura Y, Niikawa N et al (2003) PA26 is a candidate gene for heterotaxia in humans: identification of a novel PA26-related gene family in human and mouse. Hum Genet 112:573–580

    CAS  PubMed  Google Scholar 

  84. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN et al (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146:408–420

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B (1997) A model for p53-induced apoptosis. Nature 389:300–305

    CAS  PubMed  Google Scholar 

  86. Pugacheva EN, Ivanov AV, Kravchenko JE, Kopnin BP, Levine AJ, Chumakov PM (2002) Novel gain of function activity of p53 mutants: activation of the dUTPase gene expression leading to resistance to 5-fluorouracil. Oncogene 21:4595–4600

    CAS  PubMed  Google Scholar 

  87. Reid MA, Wang WI, Rosales KR, Welliver MX, Pan M, Kong M (2013) The B55alpha subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Mol Cell 50:200–211

    CAS  PubMed  Google Scholar 

  88. Reliene R, Fischer E, Schiestl RH (2004) Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice. Cancer Res 64:5148–5153

    CAS  PubMed  Google Scholar 

  89. Rufini A, Niklison-Chirou MV, Inoue S, Tomasini R, Harris IS, Marino A, Federici M, Dinsdale D, Knight RA, Melino G et al (2012) TAp73 depletion accelerates aging through metabolic dysregulation. Genes Dev 26:2009–2014

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM (2005) The antioxidant function of the p53 tumor suppressor. Nat Med 11:1306–1313

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Schubert R, Erker L, Barlow C, Yakushiji H, Larson D, Russo A, Mitchell JB, Wynshaw-Boris A (2004) Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice. Hum Mol Genet 13:1793–1802

    CAS  PubMed  Google Scholar 

  92. Selivanova G (2004) p53: fighting cancer. Curr Cancer Drug Targets 4:385–402

    CAS  PubMed  Google Scholar 

  93. Semenza GL (2012) Hypoxia-inducible factors in physiology and medicine. Cell 148:399–408

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Sen N, Satija YK, Das S (2011) PGC-1alpha, a key modulator of p53, promotes cell survival upon metabolic stress. Mol Cell 44:621–634

    CAS  PubMed  Google Scholar 

  95. Seo YR, Kelley MR, Smith ML (2002) Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. Proc Natl Acad Sci U S A 99:14548–14553

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y et al (2010) Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A 107:7461–7466

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D’Amelio M, Criollo A, Morselli E, Zhu C, Harper F et al (2008) Regulation of autophagy by cytoplasmic p53. Nat Cell Biol 10:676–687

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Vahsen N, Cande C, Briere JJ, Benit P, Joza N, Larochette N, Mastroberardino PG, Pequignot MO, Casares N, Lazar V et al (2004) AIF deficiency compromises oxidative phosphorylation. EMBO J 23:4679–4689

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Velasco-Miguel S, Buckbinder L, Jean P, Gelbert L, Talbott R, Laidlaw J, Seizinger B, Kley N (1999) PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. Oncogene 18:127–137

    CAS  PubMed  Google Scholar 

  100. Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ, Adams JM, Strasser A (2003) p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302:1036–1038

    CAS  PubMed  Google Scholar 

  101. Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8:275–283

    CAS  PubMed  Google Scholar 

  102. Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137:413–431

    CAS  PubMed  Google Scholar 

  103. Wang PY, Ma W, Park JY, Celi FS, Arena R, Choi JW, Ali QA, Tripodi DJ, Zhuang J, Lago CU et al (2013) Increased oxidative metabolism in the Li-Fraumeni syndrome. N Engl J Med 368:1027–1032

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Wei CL, Wu Q, Vega VB, Chiu KP, Ng P, Zhang T, Shahab A, Yong HC, Fu Y, Weng Z et al (2006) A global map of p53 transcription-factor binding sites in the human genome. Cell 124:207–219

    CAS  PubMed  Google Scholar 

  105. Wood ZA, Poole LB, Karplus PA (2003) Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science 300:650–653

    CAS  PubMed  Google Scholar 

  106. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484

    CAS  PubMed  Google Scholar 

  107. Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D (1996) Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 10:2411–2422

    CAS  PubMed  Google Scholar 

  108. Yoon KA, Nakamura Y, Arakawa H (2004) Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J Hum Genet 49:134–140

    CAS  PubMed  Google Scholar 

  109. Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, Hu W, Feng Z (2011) Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci U S A 108:16259–16264

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

This work is supported by NIH NCI 1RO1CA172660 to Andrei Budanov. The author thanks Brittany Binion for the help in preparation of the manuscript. The author is especially grateful to Nadulya Pryadilova for everyday support.

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  1. Department of Neurosurgery & Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

    Andrei V. Budanov

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  1. Andrei V. Budanov
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Correspondence to Andrei V. Budanov .

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  1. Department of Biochemistry and Molecular Biology, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

    Swati Palit Deb

  2. Department of Biochemistry and Molecular Biology, and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA

    Sumitra Deb

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Budanov, A.V. (2014). The Role of Tumor Suppressor p53 in the Antioxidant Defense and Metabolism. In: Deb, S., Deb, S. (eds) Mutant p53 and MDM2 in Cancer. Subcellular Biochemistry, vol 85. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9211-0_18

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