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PMID:23334421

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Citation

Jiang, P, Du, W, Mancuso, A, Wellen, KE and Yang, X (2013) Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493:689-93

Abstract

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.

Links

PubMed PMC3561500 Online version:10.1038/nature11776

Keywords

3T3 Cells; Animals; Antibiotics, Antineoplastic/pharmacology; Cell Aging/physiology; Cell Line; Cell Line, Tumor; Cell Proliferation; Doxorubicin/pharmacology; Gene Expression Regulation; Gene Knockdown Techniques; Gene Silencing; Glucose/metabolism; Glutamine/metabolism; HCT116 Cells; Humans; Lipids/biosynthesis; Malate Dehydrogenase/genetics; Malate Dehydrogenase/metabolism; Malate Dehydrogenase (NADP+)/genetics; Malate Dehydrogenase (NADP+)/metabolism; Mice; NADP/metabolism; Protein Binding/drug effects; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MAOX

GO:0004470: malic enzyme activity

ECO:0000315:

F

Fig 1C.

complete
CACAO 7031

HUMAN:MAOX

GO:1902031: regulation of NADP metabolic process

ECO:0000315:

P

In figure 2, it is shown that relative to Malic Enzyme mutants that show no enzymatic activity, wild type Malic Enzyme leads to greater production of NADPH in a cell.

complete
CACAO 7477

HUMAN:MAOX

enables

GO:0004470: malic enzyme activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MAOX

involved_in

GO:1902031: regulation of NADP metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MAOM

GO:0004470: malic enzyme activity

ECO:0000315:

F

Fig 1C.

complete
CACAO 7038

HUMAN:MAOM

GO:1902031: regulation of NADP metabolic process

ECO:0000315:

P

As shown in figure 2, the level of NADPH in the cell is comparatively greater in cells with wild type Malic Enzyme 2 than with Malic Enzyme 2 mutants that had no enzymatic activity.

complete
CACAO 7478

HUMAN:MAOM

enables

GO:0004470: malic enzyme activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:MAOM

involved_in

GO:1902031: regulation of NADP metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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