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p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase


Cancer cells consume large quantities of glucose and primarily use glycolysis for ATP production, even in the presence of adequate oxygen1,2. This metabolic signature (aerobic glycolysis or the Warburg effect) enables cancer cells to direct glucose to biosynthesis, supporting their rapid growth and proliferation3,4. However, both causes of the Warburg effect and its connection to biosynthesis are not well understood. Here we show that the tumour suppressor p53, the most frequently mutated gene in human tumours, inhibits the pentose phosphate pathway5 (PPP). Through the PPP, p53 suppresses glucose consumption, NADPH production and biosynthesis. The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer. Tumour-associated p53 mutants lack the G6PD-inhibitory activity. Therefore, enhanced PPP glucose flux due to p53 inactivation may increase glucose consumption and direct glucose towards biosynthesis in tumour cells.

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Figure 1: p53 deficiency correlates with increases in PPP flux, glucose consumption and lactate production.
Figure 2: p53 regulates NADPH levels, lipid accumulation and G6PD activity.
Figure 3: p53 interacts with G6PD and inhibits its activity independently of transcription.
Figure 4: p53 inhibits the formation of dimeric G6PD holoenzyme.
Figure 5: p53 suppresses G6PD through transient interaction and at substoichiometric ratios.


  1. Warburg, O., Posener, K. & Negelein, E. Ueber den Stoffwechsel der Tumoren. Biochem. Z. 152, 319–344 (1924).

    Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  4. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    CAS  Article  Google Scholar 

  5. Berg, J. M., Tymoczko, J. L. & Stryer, L. Biochemistry 6th edn 577–589 (W. H. Freeman, 2006).

    Google Scholar 

  6. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000).

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Google Scholar 

  9. Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006).

    CAS  Article  Google Scholar 

  10. Vousden, K. H. & Ryan, K. M. p53 and metabolism. Nat. Rev. Cancer 9, 691–700 (2009).

    CAS  Article  Google Scholar 

  11. Bunz, F. et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282, 1497–1501 (1998).

    CAS  Article  Google Scholar 

  12. Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008).

    CAS  Article  Google Scholar 

  13. Komarov, P. G. et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285, 1733–1737 (1999).

    CAS  Article  Google Scholar 

  14. Inga, A. & Resnick, M. A. Novel human p53 mutations that are toxic to yeast can enhance transactivation of specific promoters and reactivate tumor p53 mutants. Oncogene 20, 3409–3419 (2001).

    CAS  Article  Google Scholar 

  15. Freedman, D. A. & Levine, A. J. Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Mol. Cell Biol. 18, 7288–7293 (1998).

    CAS  Article  Google Scholar 

  16. Stommel, J. M. et al. A leucine-rich nuclear export signal in the p53 tetramerization domain: Regulation of subcellular localization and p53 activity by NES masking. EMBO J. 18, 1660–1672 (1999).

    CAS  Article  Google Scholar 

  17. Yan, W. & Chen, X. Characterization of functional domains necessary for mutant p53 gain of function. J. Biol. Chem. 285, 14229–14238 (2010).

    CAS  Article  Google Scholar 

  18. Nikolova, P. V., Henckel, J., Lane, D. P. & Fersht, A. R. Semirational design of active tumor suppressor p53 DNA binding domain with enhanced stability. Proc. Natl Acad. Sci. USA 95, 14675–14680 (1998).

    CAS  Article  Google Scholar 

  19. Au, S. W., Gover, S., Lam, V. M. & Adams, M. J. Human glucose-6-phosphate dehydrogenase: The crystal structure reveals a structural NADP(+) molecule and provides insights into enzyme deficiency. Structure 8, 293–303 (2000).

    CAS  Article  Google Scholar 

  20. Roos, D. et al. Molecular basis and enzymatic properties of glucose 6-phosphate dehydrogenase volendam, leading to chronic nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections. Blood 94, 2955–2962 (1999).

    CAS  PubMed  Google Scholar 

  21. Green, D. R. & Kroemer, G. Cytoplasmic functions of the tumour suppressor p53. Nature 458, 1127–1130 (2009).

    CAS  Article  Google Scholar 

  22. Bensaad, K. et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006).

    CAS  Article  Google Scholar 

  23. Tang, J. et al. Critical role for Daxx in regulating Mdm2. Nat. Cell Biol. 8, 855–862 (2006).

    CAS  Article  Google Scholar 

  24. Mancuso, A., Sharfstein, S. T., Tucker, S. N., Clark, D. S. & Blanch, H. W. Examination of primary metabolic pathways in a murine hybridoma with carbon-13 nuclear magnetic resonance spectroscopy. Biotechnol. Bioeng. 44, 563–585 (1994).

    CAS  Article  Google Scholar 

  25. Brummelkamp, T. R., Bernards, R. & Agami, R. A system for stableexpression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002).

    CAS  Article  Google Scholar 

  26. Tian, W. N. et al. Importance of glucose-6-phosphate dehydrogenase activity for cell growth. J. Biol. Chem. 273, 10609–10617 (1998).

    CAS  Article  Google Scholar 

  27. Adorno, M. et al. A mutant-p53/Smad complex opposes p63 to empower TGF β-induced metastasis. Cell 137, 87–98 (2009).

    CAS  Article  Google Scholar 

  28. Du, W. et al. Suppression of p53 activity by Siva1. Cell Death Differ. 16, 1493–1504 (2009).

    CAS  Article  Google Scholar 

  29. Tang, J. et al. A novel transcription regulatory complex containing death domain-associated protein and the ATR-X syndrome protein. J. Biol. Chem. 279, 20369–20377 (2004).

    CAS  Article  Google Scholar 

  30. Zhang, Z., Yu, J. & Stanton, R. C. A method for determination of pyridine nucleotides using a single extract. Anal. Biochem. 285, 163–167 (2000).

    CAS  Article  Google Scholar 

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We thank W. Xie for isolating p53+/+ and p53−/− MEF cells; X. Chen for SW480 cells; B. Vogelstein and W. El-Deiry for HCT116 cells; J. Cross, N. Li, J. Wu, Y. Mei, A. Stonestrom, W. Tan, H. Liu, Y. Hao, X. Zhao and Z. Lou for technical assistance; C. B. Thompson and J. Delikatny for helpful comments; and A. Stonestrom and E. Thompson for help with manuscript preparation. Supported by grants from the China National Natural Science Foundation (31030046), the Ministry of Science and Technology (2010CB912804 and 2011CB966302) and the Chinese Academy of Sciences (KSCX1-YW-R-57) to M.W. and the US National Institutes of Health (CA088868 and GM060911) and the Department of Defense (W81XWH-07-1-0336 and W81XWH-10-1-0468) to X.Y.

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P.J., W.D., M.W. and X.Y. designed the experiments and interpreted results. P.J. and W.D. carried out all the experiments, except those mentioned below. X.W. carried out the experiments on G6PD activity in yeast, the surface plasmon resonance, and lipid droplets in mouse liver. A.M. and P.J. analysed the oxidative PPP flux. X.G. supplied the p53 wild-type and knockout mice. X.Y. wrote the manuscript with the help of P.J. and W.D.

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Correspondence to Mian Wu or Xiaolu Yang.

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The authors declare no competing financial interests.

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

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