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Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence

Nature volume 493, pages 689–693 (2013)Cite this article

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Abstract

Cellular senescence both protects multicellular organisms from cancer and contributes to their ageing1. The pre-eminent tumour suppressor p53 has an important role in the induction and maintenance of senescence, but how it carries out this function remains poorly understood1,2,3. In addition, although increasing evidence supports the idea that metabolic changes underlie many cell-fate decisions and p53-mediated tumour suppression, few connections between metabolic enzymes and senescence have been established. Here we describe a new mechanism by which p53 links these functions. We show that p53 represses the expression of the tricarboxylic-acid-cycle-associated malic enzymes ME1 and ME2 in human and mouse cells. Both malic enzymes are important for NADPH production, lipogenesis and glutamine metabolism, but ME2 has a more profound effect. Through the inhibition of malic enzymes, p53 regulates cell metabolism and proliferation. Downregulation of ME1 and ME2 reciprocally activates p53 through distinct MDM2- and AMP-activated protein kinase-mediated mechanisms in a feed-forward manner, bolstering this pathway and enhancing p53 activation. Downregulation of ME1 and ME2 also modulates the outcome of p53 activation, leading to strong induction of senescence, but not apoptosis, whereas enforced expression of either malic enzyme suppresses senescence. Our findings define physiological functions of malic enzymes, demonstrate a positive-feedback mechanism that sustains p53 activation, and reveal a connection between metabolism and senescence mediated by p53.

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Figure 1: p53 represses the expression of malic enzymes.
Figure 2: ME1 and ME2 influence NADPH production, lipid production and glutaminolysis.
Figure 3: A role for malic enzymes in suppressing p53-mediated senescence.
Figure 4: Mechanisms of p53 activation induced by malic enzyme downregulation and a role of malic enzymes in tumour growth.

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Acknowledgements

We thank M. J. Birnbaum, B. Vogelstein, W. El-Deiry and M. Lazar for reagents; M. J. Bennett, S. Patel, A. Stonestrom and M. Brewer for technical assistance; and A. Stonestrom for help with manuscript preparation. This work was supported by grants from the National Institutes of Health (CA088868) and the US Department of Defense (W81XWH-10-1-0468) to X.Y.

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  1. Peng Jiang and Wenjing Du: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Peng Jiang, Wenjing Du, Anthony Mancuso, Kathryn E. Wellen & Xiaolu Yang

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  1. Peng Jiang
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Contributions

P.J., W.D. and X.Y. designed the study, interpreted the data and wrote the manuscript. P.J. and W.D. performed the experiments. K.E.W. helped with the metabolic studies and data interpretation. A.M. designed the glutaminolytic flux procedure and performed the experiment with the help from P.J.

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Correspondence to Xiaolu Yang.

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The authors declare no competing financial interests.

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Jiang, P., Du, W., Mancuso, A. et al. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493, 689–693 (2013). https://doi.org/10.1038/nature11776

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