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

Abstract

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.

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Acknowledgements

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.

Corresponding authors

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). https://doi.org/10.1038/ncb2172

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