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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Campisi, J. & d’Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nature Rev. Mol. Cell Biol. 8, 729–740 (2007)
Vousden, K. H. & Prives, C. Blinded by the light: the growing complexity of p53. Cell 137, 413–431 (2009)
Ben-Porath, I. & Weinberg, R. A. The signals and pathways activating cellular senescence. Int. J. Biochem. Cell Biol. 37, 961–976 (2005)
Jiang, P. et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nature Cell Biol. 13, 310–316 (2011)
Hsu, R. Y. Pigeon liver malic enzyme. Mol. Cell. Biochem. 43, 3–26 (1982)
Chang, G. G. & Tong, L. Structure and function of malic enzymes, a new class of oxidative decarboxylases. Biochemistry 42, 12721–12733 (2003)
Pongratz, R. L., Kibbey, R. G., Shulman, G. I. & Cline, G. W. Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. J. Biol. Chem. 282, 200–207 (2007)
Riley, T., Sontag, E., Chen, P. & Levine, A. Transcriptional control of human p53-regulated genes. Nature Rev. Mol. Cell Biol. 9, 402–412 (2008)
Murphy, M. et al. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev. 13, 2490–2501 (1999)
Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009)
Ferbeyre, G. et al. PML is induced by oncogenic ras and promotes premature senescence. Genes Dev. 14, 2015–2027 (2000)
Pearson, M. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207–210 (2000)
Brady, C. A. et al. Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell 145, 571–583 (2011)
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997)
Wei, W., Hemmer, R. M. & Sedivy, J. M. Role of p14ARF in replicative and induced senescence of human fibroblasts. Mol. Cell. Biol. 21, 6748–6757 (2001)
Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005)
Blättler, S. M., Rencurel, F., Kaufmann, M. R. & Meyer, U. A. In the regulation of cytochrome P450 genes, phenobarbital targets LKB1 for necessary activation of AMP-activated protein kinase. Proc. Natl Acad. Sci. USA 104, 1045–1050 (2007)
Wasilenko, W. J. & Marchok, A. C. Malic enzyme and malate dehydrogenase activities in rat tracheal epithelial cells during the progression of neoplasia. Cancer Lett. 28, 35–42 (1985)
Sauer, L. A., Dauchy, R. T., Nagel, W. O. & Morris, H. P. Mitochondrial malic enzymes. Mitochondrial NAD(P)+-dependent malic enzyme activity and malate-dependent pyruvate formation are progression-linked in Morris hepatomas. J. Biol. Chem. 255, 3844–3848 (1980)
Nagel, W. O., Dauchy, R. T. & Sauer, L. A. Mitochondrial malic enzymes. An association between NAD(P)+-dependent malic enzyme and cell renewal in Sprague-Dawley rat tissues. J. Biol. Chem. 255, 3849–3854 (1980)
Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005)
Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005)
Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007)
Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007)
Li, T. et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269–1283 (2012)
Brummelkamp, T. R., Bernards, R. & Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002)
Ventura, A. et al. Cre-lox-regulated conditional RNA interference from transgenes. Proc. Natl Acad. Sci. USA 101, 10380–10385 (2004)
Godar, S. et al. Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell 134, 62–73 (2008)
Jiang, P., Du, W., Heese, K. & Wu, M. The Bad guy cooperates with good cop p53: Bad is transcriptionally up-regulated by p53 and forms a Bad/p53 complex at the mitochondria to induce apoptosis. Mol. Cell. Biol. 26, 9071–9082 (2006)
Guay, C., Madiraju, S. R., Aumais, A., Joly, E. & Prentki, M. A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion. J. Biol. Chem. 282, 35657–35665 (2007)
Millard, P., Letisse, F., Sokol, S. & Portais, J. C. IsoCor: correcting MS data in isotope labeling experiments. Bioinformatics 28, 1294–1296 (2012)
Cossarizza, A. et al. Simultaneous analysis of reactive oxygen species and reduced glutathione content in living cells by polychromatic flow cytometry. Nature Protocols 4, 1790–1797 (2009)
Zhang, J. et al. AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts. J. Clin. Invest. 117, 2962–2973 (2007)
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.
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
This file contains Supplementary Figures 1-25 and additional references. (PDF 4841 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature11776
This article is cited by
-
SIRT5-mediated ME2 desuccinylation promotes cancer growth by enhancing mitochondrial respiration
Cell Death & Differentiation (2024)
-
A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism
Nature Metabolism (2024)
-
AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis
Nature Communications (2024)
-
Metabolic reprogramming in colorectal cancer: regulatory networks and therapy
Cell & Bioscience (2023)
-
Cuproptosis: p53-regulated metabolic cell death?
Cell Death & Differentiation (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.