Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

p53 and metabolism

Nature Reviews Cancer volume 9, pages 691–700 (2009)Cite this article

Key Points

  • Metabolic alterations are common features of cancer cells and have recently been shown to have an important role in the maintenance of malignancies.

  • p53 is a key tumour suppressor protein that has a diverse range of functions — including the ability to promote apoptosis, senescence and DNA repair — each of which helps to prevent cancer development. A role for p53 in regulating metabolic pathways has also recently been identified, suggesting that this is another mechanism by which p53 helps to stall malignant progression.

  • Several functions of p53 promote oxidative phosphorylation and dampen glycolysis in cells; disruption of this balance is associated with mutations in p53 and oncogenic transformation.

  • p53 also has a key role in regulating cell growth and autophagy, thereby helping to coordinate the cell's response to nutrient starvation.

  • Altered metabolism can contribute to malignant transformation, and cancer cells become dependent on these changes. Understanding the role of p53 in the regulation of metabolism may provide some interesting potential targets for the development of new cancer therapies.

Abstract

Although metabolic alterations have been observed in cancer for almost a century, only recently have the mechanisms underlying these changes been identified and the importance of metabolic transformation realized. p53 has been shown to respond to metabolic changes and to influence metabolic pathways through several mechanisms. The contributions of these activities to tumour suppression are complex and potentially rather surprising: some reflect the function of basal p53 levels that do not require overt activation and others might even promote, rather than inhibit, tumour progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Nutrient deprivation signals to p53.
Figure 2: Regulation of energy production by p53.
Figure 3: Regulation of autophagy by p53.
Figure 4: Regulation of oxidative stress by p53.

Similar content being viewed by others

References

  1. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    Article  CAS  PubMed  Google Scholar 

  2. Zhivotovsky, B. & Orrenius, S. The Warburg Effect returns to the cancer stage. Semin. Cancer Biol. 19, 1–3 (2009).

    Article  PubMed  Google Scholar 

  3. Robey, R. B. & Hay, N. Is Akt the “Warburg kinase”? — Akt-energy metabolism interactions and oncogenesis. Semin. Cancer Biol. 19, 25–31 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Hardie, D. G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nature Rev. Mol. Cell Biol. 8, 774–785 (2007).

    Article  CAS  Google Scholar 

  5. Tenant, D. A., Durán, R. V., Boulanbel, H. & Gottlieb, E. Metabolic transformation in cancer. Carcinogenesis 30, 1269–1280 (2009).

    Article  CAS  Google Scholar 

  6. Kroemer, G. & Pouyssegur, J. Tumor cell metabolism: cancer's achilles' heel. Cancer Cell 13, 472–482 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Hsu, P. P. & Sabatini, D. M. Cancer cell metabolism: Warburg and beyond. Cell 134, 703–707 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. DeBerardinis, R. J., Lum, J. J., Hatzivassilou, G. & Thompson, C. B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell. Metab. 7, 11–20 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Young, C. D. & Anderson, S. M. Sugar and fat - that's where it's at: metabolic changes in tumors. Breast Cancer Res. 20 Feb 2008 (doi:10.1186/bcr1852).

  10. DeBerardinis, R. J., Sayed, N., Ditsworth, D. & Thompson, C. B. Brick by brick: metabolism and tumor cell growth. Curr. Opin. Genet. Dev. 18, 54–61 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pfeiffer, T., Schuster, S. & Bonhoeffer, S. Cooperation and competition in the evolution of ATP-producing pathways. Science 292, 504–507 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Fantin, V. R., Syt-Pierre, J. & Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Bonnet, S. et al. A mitochondrial-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer cell growth. Cancer Cell 11, 37–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Shakya, A. et al. Oct1 loss of function induces a coordinate metabolic shift that opposes tumorigenicity. Nature Cell Biol. 11, 320–327 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Denko, N. C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nature Rev. Cancer 8, 705–713 (2008).

    Article  CAS  Google Scholar 

  17. DeBerardinis, R. J. et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Feron, O. Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother. Oncol. 13 Jul 2009 (doi:10.1016/j.radouc.2009.06.025).

  19. Hennessy, B. T., Smith, D. L., Ram, P. T., Lu, Y. & Mills, G. B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature Rev. Drug Discov. 4, 988–1004 (2005).

    Article  CAS  Google Scholar 

  20. Plas, D. R. & Thompson, C. B. Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24, 7435–7442 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Dang, C. V., Kim, J. W., Gao, P. & Yustein, J. The interplay between MYC and HIF in cancer. Nature Rev. Cancer 8, 51–56 (2008).

    Article  CAS  Google Scholar 

  22. Yeung, S. J., Pan, J. & Lee, M. H. Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. Cell. Mol. Life Sci. 65, 3981–3999 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Wise, D. R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA 105, 18782–18787 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Horn, H. F. & Vousden, K. H. Coping with stress: multiple ways to activate p53. Oncogene 26, 1306–1316 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Vousden, K. H. & Prives, C. Blinded by the light: the growing complexity of p53. Cell 137, 413–431 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Mayo, L. D. & Donner, D. B. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem. Sci. 27, 462–467 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Stambolic, V. et al. Regulation of PTEN transcription by p53. Mol. Cell 8, 317–325 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005). This study was the first to report that the energy-sensing enzyme AMPK signals biological responses through p53.

    Article  CAS  PubMed  Google Scholar 

  30. Okoshi, R. et al. Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. J. Biol. Chem. 283, 3979–3987 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Lee, S. M., Kim, J. H., Cho, E. J. & Youn, H. D. A nucleocytoplasmic malate dehydrogenase regulates p53 transcriptional activity in response to metabolic stress. Cell Death Differ. 16, 738–748 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Okorokov, A. L. & Milner, J. An ATP/ADP-dependent molecular switch regulates the stability of p53-DNA complexes. Mol. Cell. Biol. 19, 7501–7510 (1999). This report was the first to indicate that ratios of ATP and ADP can signal to p53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kong, M. et al. The PP2A-associated protein a4 is an essential inhibitor of apoptosis. Science 306, 695–698 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Lee, C. H. et al. Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53. EMBO J. 26, 4812–4823 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhao, Y. et al. Glucose metabolism attenuates p53 and Puma-dependent cell death upon growth factor deprivation. J. Biol. Chem. 283, 36344–36353 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Alarcon, R., Koumenis, C., Geyer, R. K., Maki, C. G. & Giaccia, A. J. Hypoxia induces p53 accumulation through MDM2 down-regulation and inhibition of E6-mediated degradation. Cancer Res. 59, 6046–6051 (1999).

    CAS  PubMed  Google Scholar 

  37. An, W. G. et al. Stabilization of wild-type by hypoxia-inducible factor 1α. Nature 392, 405–408 (1998). This study was the first to report a link between p53, HIF and hypoxia.

    Article  CAS  PubMed  Google Scholar 

  38. Hammond, E. M., Denko, N. C., Dorie, M. J., Abraham, R. T. & Giaccia, A. J. Hypoxia links ATR and p53 through replication arrest. Mol. Cell. Biol. 22, 1834–1843 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pan, Y., Oprysko, P. R., Asham, A. M., Koch, C. J. & Simon, M. C. p53 cannot be induced by hypoxia alone but responds to the hypoxic microenvironment. Oncogene 23, 4975–4983 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Lindstrom, M. S., Deisenroth, C. & Zhang, Y. Putting a finger on growth surveillance: insight into MDM2 zinc finger-ribosomal protein interactions. Cell Cycle 6, 434–437 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Meplan, C., Richard, M. J. & Hainaut, P. Redox signalling and transition metals in the control of the p53 pathway. Biochem. Pharmacol. 59, 25–33 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Augustyn, K. E., Merino, E. J. & Barton, J. K. A role for DNA-mediated charge transport in regulating p53: oxidation of the DNA-bound protein from a distance. Proc. Natl Acad. Sci. USA 104, 18907–18912 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Karawajew, L., Rhein, P., Czerwony, G. & Ludwig, W. D. Stress-induced activation of the p53 tumor suppressor in leukemia cells and normal lymphocytes requires mitochondrial activity and reactive oxygen species. Blood 105, 4767–4775 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Schwartzenberg-Bar-Yoseph, F., Armoni, M. & Karnieli, E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res. 64, 2627–2633 (2004). Reported that p53 can impede metabolism at source by reducing glucose import.

    Article  CAS  PubMed  Google Scholar 

  45. Kondoh, H. et al. Glycolytic enzymes can modulate cellular lifespan. Cancer Res. 65, 177–185 (2005).

    CAS  PubMed  Google Scholar 

  46. Bensaad, K. et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006). The first report of a gene that impedes glycolysis ( TIGAR ) being activated by p53.

    Article  CAS  PubMed  Google Scholar 

  47. Kawauchi, K., Araki, K., Tobiume, K. & Tanaka, N. p53 regulates glucose metabolism though an IKK-NF-kB pathway and inhibits cell transformation. Nature Cell Biol. 10, 611–618 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Kawauchi, K., Araki, K., Tobiume, K. & Tanaka, N. Loss of p53 enhances catalytic activity of IKKβ through O-linked beta-N-acetyl glucosamine modification. Proc. Natl Acad. Sci. USA 106, 3431–3436 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kulawiec, M., Ayyasamy, V. & Singh, K. K. p53 regulates mtDNA copy number and mitocheckpoint pathway. J. Carcinog. 8, 8 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Lebedeva, M. A., Eaton, J. S. & Shadel, G. S. Loss of p53 causes mitochondrial DNA depletion and altered mitochondrial reactive oxygen species homeostasis. Biochim. Biophys. Acta 1787, 328–334 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Okamura, S. et al. Identification of seven genes regulated by wild-type p53 in a colon cancer cell line carrying a well-controlled wild-type p53 expression system. Oncol. Res. 11, 281–285 (1999).

    CAS  PubMed  Google Scholar 

  52. Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006). This report was the first to show that p53 can promote mitochondrial respiration through the transcriptional upregulation of SCO2 .

    Article  CAS  PubMed  Google Scholar 

  53. Bourdon, A. et al. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nature Genet. 39, 776–780 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Burns, D. M. & Richter, J. D. CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation. Genes Dev. 22, 3449–3460 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ruiz-Lozano, P. et al. p53 is a transcriptional activator of the muscle-specific phosphoglycerate mutase gene and contributes in vivo to the control of its cardiac expression. Cell Growth Differ. 10, 295–306 (1999).

    CAS  PubMed  Google Scholar 

  56. Mathupala, S. P., Heese, C. & Pedersen, P. L. Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J. Biol. Chem. 272, 22776–22780 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Mathupala, S. P., Ko, Y. H. & Pedersen, P. L. Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25, 4777–4786 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Buzzai, M. et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67, 6745–6752 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Levine, A. J., Feng, Z., Mak, T. W., You, H. & Jin, S. Coordination and communication between the p53 and IGF-1–AKT–TOR signal transduction pathways. Genes Dev. 20, 267–275 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. Feng, Z. et al. The regulation of AMPK β1, 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. 67, 3043–3053 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Budanov, A. V. & Karin, M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134, 451–460 (2008). Here, the identification of sestrins as p53 target genes provided the first molecular link between p53 and the regulation of AMPK and mTOR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Feng, Z., Zhang, H., Levine, A. J. & Jin, S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl Acad. Sci. USA 102, 8204–8209 (2005). This study was the first to report that p53 may promote autophagy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zeng, P. Y. & Berger, S. L. LKB1 is recruited to the p21/WAF1 promoter by p53 to mediate transcriptional activation. Cancer Res. 66, 10701–10708 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Xie, Z. & Klionsky, D. J. Autophagosome formation: core machinery and adaptations. Nature Cell Biol. 9, 1102–1109 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Levine, B. & Klionsky, D. J. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 6, 463–477 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Lum, J. J., DeBerardinis, R. J. & Thompson, C. B. Autophagy in metazoans: cell survival in the land of plenty. Nature Rev. Mol. Cell Biol. 6, 439–448 (2005).

    Article  CAS  Google Scholar 

  67. Shimizu, S. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biol. 6, 1221–1228 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Berry, D. L. & Baehrecke, E. H. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 131, 1137–1148 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yu, L. et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500–1502 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Marino, G. et al. Tissue-specific autophagy alterations and increased tumorigenesis in mice deficient in Atg4C/autophagin-3. J. Biol. Chem. 282, 18573–18583 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Degenhardt, K. et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10, 51–64 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  75. Young, A. R. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798–803 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Crighton, D. et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 14, 121–134 (2006). Here, DRAM was the first target gene of p53 to be reported to regulate autophagy.

    Article  CAS  Google Scholar 

  77. Abida, W. M. & Gu, W. p53-dependent and p53-independent activation of autophagy by ARF. Cancer Res. 68, 352–357 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tasdemir, E. et al. Regulation of autophagy by cytoplasmic p53. Nature Cell Biol. 10, 676–687 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Maiuri, M. C. et al. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ. 16, 87–93 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Yee, K. S., Wilkinson, S., James, J., Ryan, K. M. & Vousden, K. H. PUMA- and Bax-induced autophagy contributes to apoptosis. Cell Death Differ. 16, 1135–1145 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Rampino, N. et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275, 967–969 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Maiuri, M. C. et al. Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle 8, 1571–1576 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Morselli, E. et al. Mutant p53 protein localized in the cytoplasm inhibits autophagy. Cell Cycle 7, 3056–3061 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Sherr, C. J. & Weber, J. D. The ARF/p53 pathway. Curr. Opin. Genet. Dev. 10, 94–99 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Stott, F. et al. The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 17, 5001–5014 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pimkina, J., Humbey, O., Zilfou, J. T., Jarnik, M. & Murphy, M. E. ARF induces autophagy by virtue of interaction with Bcl-xl. J. Biol. Chem. 284, 2803–2810 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Olive, K. P. et al. Mutant p53 gain-of-function in two mouse models of Li-Fraumeni syndrome. Cell 119, 847–860 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Lang, G. A. et al. Gain-of-function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119, 861–872 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Gaiddon, C. et al. Cyclin-dependent kinases phosphorylate p73 at threonine 86 in a cell cycle-dependent manner and negatively regulate p73. J. Biol. Chem. 278, 27421–27431 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Crighton, D., O'Prey, J., Bell, H. S. & Ryan, K. M. p73 regulates DRAM-independent autophagy that does not contribute to programmed cell death. Cell Death Differ. 14, 1071–1079 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Sablina, A. A. et al. The antioxidant function of the p53 tumor suppressor gene. Nature Med. 11, 1306–1313 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Budanov, A. V., Sablina, A. A., Feinstein, E., Koonin, E. V. & Chumakov, P. M. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304, 596–600 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Tan, M. et al. Transcriptional activation of the human glutathione peroxidase promoter by p53. J. Biol. Chem. 274, 12061–12066 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  95. Cano, C. E. et al. Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function. Cancer Res. 69, 219–226 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Lyakhov, I. G., Krishnamachari, A. & Schneider, T. D. Discovery of novel tumor suppressor p53 response elements using information theory. Nucleic Acids Res. 36, 3828–3833 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Macip, S. et al. Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol. Cell. Biol. 23, 8576–8585 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tu, H. C. et al. The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage. Proc. Natl Acad. Sci. USA 106, 1093–1098 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W. & Vogelstein, B. A model for p53-induced apoptosis. Nature 389, 300–305 (1997).

    Article  CAS  PubMed  Google Scholar 

  100. Rivera, A. & Maxwell, S. A. The p53-induced gene-6 (proline oxidase) mediates apoptosis through a calcineurin-dependent pathway. J. Biol. Chem. 280, 29346–29354 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Liu, Z. et al. PUMA overexpression induced reactive oxygen species generation and proteasome-mediated stathmin degradation in colorectal cancer cells. Cancer Res. 65, 1647–1654 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Trinei, M. et al. A p53-p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damage DNA and oxidative stress-induced apoptosis. Oncogene 21, 3872–3878 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Drane, P., Bravard, A., Bouvard, V. & May, E. Reciprocal down-regulation of p53 and SOD2 gene expression-implication in p53 mediated apoptosis. Oncogene 20, 430–439 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Hussain, S. P. et al. p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. Cancer Res. 64, 2350–2356 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Farianio, R. et al. p53 supresses the Nrf2-dependent transcription of antioxidant response genes. J. Biol. Chem. 281, 39776–39784 (2006).

    Article  CAS  Google Scholar 

  106. Chatoo, W. et al. The polycomb group gene Bmi1 regulates antioxidant defenses in neurons by repressing p53 pro-oxidant activity. J. Neurosci. 29, 529–542 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Jones, R. G. & Thompson, C. B. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 23, 537–548 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Vousden, K. H. & Lane, D. P. p53 in health and disease. Nature Rev. Mol. Cell Biol. 8, 275–283 (2007).

    Article  CAS  Google Scholar 

  109. Janicke, R. U., Sohn, D. & Schulze-Osthoff, K. The dark side of a tumor suppressor: anti-apoptotic p53. Cell Death Differ. 15, 959–976 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Varley, J. M. Germline TP53 mutations and Li-Fraumeni syndrome. Hum. Mutat. 21, 313–320 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Bertheau, P. et al. TP53 status and response to chemotherapy in breast cancer. Pathobiology 75, 132–139 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Ungewitter, E. & Scrable, H. Antagonistic pleiotropy and p53. Mech. Ageing Dev. 130, 10–17 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Feng, Z., Hu, W., Rajagopal, G. & Levine, A. J. The tumor suppressor p53: cancer and aging. Cell Cycle 7, 842–847 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Matheu, A., Maraver, A. & Serrano, M. The Arf/p53 pathway in cancer and aging. Cancer Res. 68, 6031–6034 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Piccolo, S. p53 regulation orchestrates the TGF-β response. Cell 133, 767–769 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Sah, V. P. et al. A subset of p53-deficient embyos exhibit exencephaly. Nature Genet. 10, 175–180 (1995).

    Article  CAS  PubMed  Google Scholar 

  117. Chio, J. & Donehower, L. A. p53 in embryonic development: maintaining a fine balance. Cell. Mol. Life Sci. 55, 38–47 (1999).

    Article  Google Scholar 

  118. Meletis, K. et al. p53 suppresses the self-renewal of adult neural stem cells. Development 133, 363–369 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Liu, Y. et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell 4, 37–48 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hu, W., Feng, Z., Teresky, A. K. & Levine, A. J. p53 regulates maternal reproduction through LIF. Nature 450, 721–724 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Kang, H. J. et al. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc. Natl Acad. Sci. USA 106, 9761–9766 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Cui, R. et al. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell 128, 853–864 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Bae, B. I. et al. p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron 47, 29–41 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Bretaud, S., Allen, C., Ingham, P. W. & Bandmann, O. p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson's disease. J. Neurochem. 100, 1626–1635 (2007).

    CAS  PubMed  Google Scholar 

  125. Culmsee, C. & Landshamer, S. Molecular insights into mechanisms of the cell death program: role in the progression of neurodegenerative disorders. Curr. Alzheimer Res. 3, 269–283 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Komarova, E. A. & Gudkov, A. V. Chemoprotection from p53-dependent apoptosis: potential clinical applications of the p53 inhibitors. Biochem. Pharmacol. 62, 657–667 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Liu, P., Xu, B., Cavalieri, T. A. & Hock, C. E. Pifithrin-α attenuates p53-mediated apoptosis and improves cardiac function in response to myocardial ischemia/reperfusion in aged rats. Shock 26, 608–614 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Dagher, P. C. Apoptosis in ischemic renal injury: roles of GTP depletion and p53. Kidney Int. 66, 506–509 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Morrison, R. S. & Kinoshita, Y. The role of p53 in neuronal cell death. Cell Death Differ. 7, 868–879 (2000).

    Article  CAS  PubMed  Google Scholar 

  130. Montanaro, L., Trere, D. & Derenzini, M. Nucleolus, ribosomes, and cancer. Am. J. Pathol. 173, 301–310 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Jones, N. C. et al. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nature Med. 14, 125–133 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. McGowan, K. A. et al. Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects. Nature Genet. 40, 963–970 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. Minamino et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nature Med. 30 Aug 2009 (doi:10.1038/nm.2014).

Download references

Acknowledgements

We would like to thank E. Gottlieb and E. Cheung for reading the manuscript and support from Cancer Research UK.

Author information

Authors and Affiliations

  1. The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, G61 1BD, UK

    Karen H. Vousden & Kevin M. Ryan

  2. Karen H. Vousden & Kevin M. Ryan

Authors
  1. Karen H. Vousden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin M. Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

OMIM

Li-Fraumeni syndrome

Pathway Interaction Database 

AKT

AMPK

ARF

FURTHER INFORMATION

Karen H. Vousden's homepage

Kevin M. Ryan's homepage

Glossary

Glycolysis

The stepwise pathway that converts glucose into pyruvate with the net generation of two molecules of ATP.

Autophagy

Literally translated from greek as 'self eating'. The cellular trafficking process whereby cytoplasmic constituents are targeted to lysosomes for degradation.

Hypoxia

A decrease in ambient O2 availability and levels.

Oxidative stress

The accumulation of ROS owing to increased production, the inability of the cell to counter ROS production or both.

Glutaminolysis

The metabolic pathway that breaks down glutamine.

Catabolism

The metabolic breakdown of relatively complex molecules into simpler parts.

Necrosis

A less ordered form of cell death that is characterized by cell rupture and, in an organismal setting, an inflammatory response.

Mitophagy

The selective degradation of mitochondria by autophagy.

Anabolism

The aspect of metabolism in which more complex molecules are built from their constituent parts, such as proteins from amino acids.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vousden, K., Ryan, K. p53 and metabolism. Nat Rev Cancer 9, 691–700 (2009). https://doi.org/10.1038/nrc2715

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2715

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing