Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence
Open accessAbstract
Cellular senescence both protects multicellular organisms from cancer and contributes to their ageing. 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 understood. 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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Targeting aspects of mitochondrial biology such as the electron transport chain, complex I assembly, mitochondrial fission rates, biogenesis, mitochondrial sirtuins, and/or disruption of the TCA cycle can trigger senescence.
“Targeting aspects of mitochondrial biology, such as the electron transport chain (ETC), complex I assembly, mitochondrial fission rates, and biogenesis, mitochondrial sirtuins and/or disruption of the TCA cycle can trigger senescence (Correia-Melo et al., 2016; Jiang et al., 2013; Kaplon et al., 2013; Miwa et al., 2014; Moiseeva et al., 2009; Park et al., 2010; Wiley et al., 2016).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Jiang et al., 2013
The paper reports that depleting ME1 or the mitochondrial enzyme ME2 induces senescence, and describes both as TCA-cycle-associated (Abstract; page unavailable). This supports a link between targeting a TCA-related metabolic enzyme and senescence, but it does not establish that disruption of the TCA cycle itself triggers senescence. The other mitochondrial targets in the sentence are not findings attributed specifically to Jiang et al. (LLM, conf=0.82)
Experimental — accuracy not yet measuredME1 and ME2 expression is repressed by p53, and MEs negatively regulate p53, so ME depletion activates p53 and induces senescence.
“ME1 and ME2 expression is repressed by p53 and the MEs negatively regulate p53, thus depletion of the MEs results in p53 activation in a feed forward manner, thereby inducing senescence 50 (FIG.1).”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [50]
Malic enzymes and p53 mutually repress one another.
“This study shows that Malic enzymes (MEs) and p53 reciprocally repress each other”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [50]
Loss of ME1 or ME2 triggers senescence in normal and tumour cells alike.
“and that depletion of ME1 or ME2 induces senescence in both normal and tumour cells.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [50]
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- Authors
- Jiang, P., Du, W., Mancuso, A., Wellen, K. E., & Yang, X.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Yang, Xiaolu
- Venue
- Nature
- Published
- 2013-01
- Volume
- 493
- Issue
- 7434
- Pages
- 689-693
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3561500
- OpenAlex
- W2039378889
- Cited by
- 491
- References
- 33
- Citations by year
- 2026: 23 · 2025: 37 · 2024: 33 · 2023: 35 · 2022: 39 · 2021: 41 · 2020: 41 · 2019: 37 · 2018: 34 · 2017: 32 · 2016: 35 · 2015: 32 · 2014: 49 · 2013: 22
- FWCI
- 31.94
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (R01CA088868, CA088868, P30CA016520)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- p53, malic enzyme, ME1, cellular senescence, NADPH production, lipogenesis, glutamine metabolism, TCA cycle, MDM2, AMPK, positive feedback loop, tumor suppression, cellular metabolism, cell proliferation
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Cell Line, Doxorubicin, Gene Expression Regulation, Glucose, Glutamine, Humans, Lipids, Malate Dehydrogenase, NADP, Protein Binding, Tumor Suppressor Protein p53, 3T3 Cells, Cellular Senescence, Gene Silencing, HCT116 Cells, Cell Line, Tumor, Cell Proliferation, Malate Dehydrogenase (NADP+), Mice, Gene Knockdown Techniques
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