Home LiteratureArticle Details
PMID: 20399660 Published · ppublish English Journal Article Review

The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein.

Trends in cell biology ·Vol. 20 ·No. 7 ·2010-07-00 ·Pages 427-34

Feng Z, Levine AJ

Abstract

In response to stress, p53 initiates the transcriptional regulation of selected target genes and various cellular responses, including cell cycle arrest, apoptosis and senescence. Recent studies revealed two additional functions of p53 in the regulation of IGF-1/AKT/mTOR pathways and energy metabolism, contributing to p53's role as a tumor suppressor. Oncogenic processes give rise to metabolic pathways focused upon the use of aerobic glycolysis (the Warburg effect) and the pentose shunt, providing higher levels of reducing activities. p53 shuts down these pathways and refocuses cells to utilize mitochondrial oxidative phosphorylation, thereby maximizing efficient ATP production and minimizing the synthesis of substrates for cell division. The use of these alternative metabolic pathways is an integral part of both normal and oncogenic phenotypes.

MeSH Terms
Animals Energy Metabolism Humans Insulin-Like Growth Factor I/metabolism Intracellular Signaling Peptides and Proteins/metabolism Neoplasms/metabolism Protein Serine-Threonine Kinases/metabolism Signal Transduction Stress, Physiological TOR Serine-Threonine Kinases Tumor Suppressor Protein p53/genetics,metabolism
Chemicals
Intracellular Signaling Peptides and Proteins Tumor Suppressor Protein p53 Insulin-Like Growth Factor I MTOR protein, human Protein Serine-Threonine Kinases TOR Serine-Threonine Kinases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Feng Zhaohui
Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA. [email protected]
Levine Arnold J
References (82)
82 references, click to expand
  1. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD.
    Science. 2004 Apr 23;304(5670):596-600 PMID: 15105503
  2. Blinded by the Light: The Growing Complexity of p53.
    Cell. 2009 May 1;137(3):413-31 PMID: 19410540
  3. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action.
    Cell. 2002 Jul 26;110(2):177-89 PMID: 12150926
  4. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling.
    Cell. 2008 Aug 8;134(3):451-60 PMID: 18692468
  5. AMPK and Raptor: matching cell growth to energy supply.
    Mol Cell. 2008 May 9;30(3):263-5 PMID: 18471972
  6. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation.
    Nat Cell Biol. 2001 Nov;3(11):973-82 PMID: 11715018
  7. hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase.
    J Biol Chem. 2005 Sep 23;280(38):33076-82 PMID: 16049009
  8. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses.
    J Hum Genet. 2004;49(3):134-140 PMID: 14986171
  9. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton.
    Curr Biol. 2004 Jul 27;14(14):1296-302 PMID: 15268862
  10. Targeting HIF-1 for cancer therapy.
    Nat Rev Cancer. 2003 Oct;3(10):721-32 PMID: 13130303
  11. Cell cycle regulation via p53 phosphorylation by a 5'-AMP activated protein kinase activator, 5-aminoimidazole- 4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line.
    Biochem Biophys Res Commun. 2001 Sep 21;287(2):562-7 PMID: 11554766
  12. p53 regulates mitochondrial respiration.
    Science. 2006 Jun 16;312(5780):1650-3 PMID: 16728594
  13. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.
    Genes Dev. 2004 Dec 1;18(23):2893-904 PMID: 15545625
  14. A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity.
    Nature. 2009 Aug 27;460(7259):1149-53 PMID: 19668189
  15. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity.
    Cell. 2006 Oct 6;127(1):125-37 PMID: 16962653
  16. p53 regulates mtDNA copy number and mitocheckpoint pathway.
    J Carcinog. 2009;8:8 PMID: 19439913
  17. Cancer cell metabolism: Warburg and beyond.
    Cell. 2008 Sep 5;134(5):703-7 PMID: 18775299
  18. PUMA- and Bax-induced autophagy contributes to apoptosis.
    Cell Death Differ. 2009 Aug;16(8):1135-45 PMID: 19300452
  19. The PP2A-associated protein alpha4 is an essential inhibitor of apoptosis.
    Science. 2004 Oct 22;306(5696):695-8 PMID: 15499020
  20. Glycolytic enzymes can modulate cellular life span.
    Cancer Res. 2005 Jan 1;65(1):177-85 PMID: 15665293
  21. Ras, PI(3)K and mTOR signalling controls tumour cell growth.
    Nature. 2006 May 25;441(7092):424-30 PMID: 16724053
  22. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR.
    Mol Cell. 2003 Apr;11(4):895-904 PMID: 12718876
  23. Targeting PI3K signalling in cancer: opportunities, challenges and limitations.
    Nat Rev Cancer. 2009 Aug;9(8):550-62 PMID: 19629070
  24. The regulation of exosome secretion: a novel function of the p53 protein.
    Cancer Res. 2006 May 1;66(9):4795-801 PMID: 16651434
  25. Energy deregulation: licensing tumors to grow.
    Science. 2006 May 26;312(5777):1158-9 PMID: 16728625
  26. Autophagy in the pathogenesis of disease.
    Cell. 2008 Jan 11;132(1):27-42 PMID: 18191218
  27. Why do cancers have high aerobic glycolysis?
    Nat Rev Cancer. 2004 Nov;4(11):891-9 PMID: 15516961
  28. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.
    Nature. 2008 Mar 13;452(7184):230-3 PMID: 18337823
  29. The P53 pathway: what questions remain to be explored?
    Cell Death Differ. 2006 Jun;13(6):1027-36 PMID: 16557269
  30. Akt stimulates aerobic glycolysis in cancer cells.
    Cancer Res. 2004 Jun 1;64(11):3892-9 PMID: 15172999
  31. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive.
    Nat Cell Biol. 2004 Nov;6(11):1122-8 PMID: 15467718
  32. Glucose metabolism and cancer.
    Curr Opin Cell Biol. 2006 Dec;18(6):598-608 PMID: 17046224
  33. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways.
    Cancer Res. 2007 Apr 1;67(7):3043-53 PMID: 17409411
  34. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage.
    Nature. 2000 Mar 2;404(6773):42-9 PMID: 10716435
  35. Regulation of PTEN transcription by p53.
    Mol Cell. 2001 Aug;8(2):317-25 PMID: 11545734
  36. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells.
    Nature. 2009 Aug 27;460(7259):1145-8 PMID: 19668190
  37. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion.
    Nat Genet. 2007 Jun;39(6):776-80 PMID: 17486094
  38. Akt-dependent transformation: there is more to growth than just surviving.
    Oncogene. 2005 Nov 14;24(50):7435-42 PMID: 16288290
  39. The LKB1 tumor suppressor negatively regulates mTOR signaling.
    Cancer Cell. 2004 Jul;6(1):91-9 PMID: 15261145
  40. Growing roles for the mTOR pathway.
    Curr Opin Cell Biol. 2005 Dec;17(6):596-603 PMID: 16226444
  41. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway.
    Nature. 2009 Aug 27;460(7259):1132-5 PMID: 19668191
  42. Autophagy fights disease through cellular self-digestion.
    Nature. 2008 Feb 28;451(7182):1069-75 PMID: 18305538
  43. Regulation of Akt/PKB Ser473 phosphorylation.
    Mol Cell. 2005 Apr 15;18(2):143-5 PMID: 15837416
  44. Regulation of protein synthesis by ionizing radiation.
    Mol Cell Biol. 2009 Nov;29(21):5645-56 PMID: 19704005
  45. p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation.
    Nat Cell Biol. 2008 May;10(5):611-8 PMID: 18391940
  46. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis.
    Nat Rev Cancer. 2006 Mar;6(3):184-92 PMID: 16453012
  47. Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair.
    Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):424-8 PMID: 9892649
  48. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF.
    Mol Cell Biol. 2003 Dec;23(23):8862-77 PMID: 14612424
  49. Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B.
    Mol Cell Biol. 2002 Sep;22(17):6247-60 PMID: 12167717
  50. Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53.
    EMBO J. 2007 Nov 28;26(23):4812-23 PMID: 17962806
  51. Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways.
    Genes Dev. 2006 Feb 1;20(3):267-75 PMID: 16452501
  52. Oncogenic PI3K deregulates transcription and translation.
    Nat Rev Cancer. 2005 Dec;5(12):921-9 PMID: 16341083
  53. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery.
    Cell. 2002 Jul 26;110(2):163-75 PMID: 12150925
  54. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans.
    Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9761-6 PMID: 19470478
  55. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption.
    Cell Metab. 2006 Mar;3(3):187-97 PMID: 16517406
  56. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression.
    Cancer Res. 2004 Apr 1;64(7):2627-33 PMID: 15059920
  57. The regulation of the endosomal compartment by p53 the tumor suppressor gene.
    FEBS J. 2009 Apr;276(8):2201-12 PMID: 19302216
  58. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG.
    Nat Cell Biol. 2006 Jul;8(7):688-99 PMID: 16799551
  59. P53 is a tumor suppressor gene.
    Cell. 2004 Jan 23;116(2 Suppl):S67-9, 1 p following S69 PMID: 15055586
  60. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase.
    J Biol Chem. 2005 Jul 15;280(28):26089-93 PMID: 15905173
  61. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.
    Nat Cell Biol. 2002 Sep;4(9):648-57 PMID: 12172553
  62. The coordinate regulation of the p53 and mTOR pathways in cells.
    Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8204-9 PMID: 15928081
  63. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.
    Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15077-82 PMID: 14657337
  64. p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease.
    Neuron. 2005 Jul 7;47(1):29-41 PMID: 15996546
  65. Transcriptional activation of the human glutathione peroxidase promoter by p53.
    J Biol Chem. 1999 Apr 23;274(17):12061-6 PMID: 10207030
  66. Mutant p53 protein localized in the cytoplasm inhibits autophagy.
    Cell Cycle. 2008 Oct;7(19):3056-61 PMID: 18818522
  67. TSC2 mediates cellular energy response to control cell growth and survival.
    Cell. 2003 Nov 26;115(5):577-90 PMID: 14651849
  68. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function.
    Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7455-60 PMID: 20378837
  69. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.
    Cell Metab. 2006 Mar;3(3):177-85 PMID: 16517405
  70. Growth factor regulation of autophagy and cell survival in the absence of apoptosis.
    Cell. 2005 Jan 28;120(2):237-48 PMID: 15680329
  71. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism.
    Cell Metab. 2005 Jan;1(1):15-25 PMID: 16054041
  72. p53 tumor suppressor protein regulates the levels of huntingtin gene expression.
    Oncogene. 2006 Jan 5;25(1):1-7 PMID: 16278683
  73. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis.
    Cell. 2006 Jul 14;126(1):121-34 PMID: 16839881
  74. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.
    Cell. 2005 Nov 18;123(4):569-80 PMID: 16286006
  75. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.
    Science. 2005 Feb 18;307(5712):1098-101 PMID: 15718470
  76. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth.
    Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6658-63 PMID: 9192621
  77. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species.
    Mol Cell. 2002 Nov;10(5):995-1005 PMID: 12453409
  78. p53 regulates maternal reproduction through LIF.
    Nature. 2007 Nov 29;450(7170):721-4 PMID: 18046411
  79. TIGAR, a p53-inducible regulator of glycolysis and apoptosis.
    Cell. 2006 Jul 14;126(1):107-20 PMID: 16839880
  80. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.
    Mol Cell. 2005 Apr 29;18(3):283-93 PMID: 15866171
  81. On the origin of cancer cells.
    Science. 1956 Feb 24;123(3191):309-14 PMID: 13298683
  82. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.
    Cancer Cell. 2006 Jun;9(6):425-34 PMID: 16766262
Article Info
Journal
Trends in cell biology
Abbr.
Trends Cell Biol
ISSN
1879-3088
DOI
10.1016/j.tcb.2010.03.004
Email
[email protected]
Published
2010-07-00
Pages
427-34
Language
English
Region
England
NLM ID
9200566
PMCID
PMC2921989
Subset
IM
Grants
NCI NIH HHS · P01 CA087497-090002 · United States
NCI NIH HHS · R01 CA143204 · United States
NCI NIH HHS · R01 CA143204-01 · United States
External Links
PubMed source DOI: 10.1016/j.tcb.2010.03.004 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2