Jiang P, Du W, Mancuso A et al.Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493:689-693

1] Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA [2].
Nature (Impact Factor: 41.46). 01/2013; 493(7434). DOI: 10.1038/nature11776
Source: PubMed


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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    • "Heterologous expression of M. circinelloides ME in R. glutinis also significantly promoted lipid accumulation (Li et al., 2013). Overexpression of ME enhanced tumor cell growth and depletion of ME strongly impaired tumor cell growth and quantity (Jiang et al., 2013). However, we found a slightly lower growth rate in PtMEoverexpressing P. tricornutum, which we believe was due to the over storage of lipid. "
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    ABSTRACT: To obtain fast growing oil-rich microalgal strains has been urgently demanded for microalgal biofuel. Malic enzyme (ME), which is involved in pyruvate metabolism and carbon fixation, was first characterized in microalgae here. Overexpression of Phaeodactylum tricornutum ME (PtME) significantly enhanced the expression of PtME and its enzymatic activity in transgenic P. tricornutum. The total lipid content in transgenic cells markedly increased by 2.5-fold and reached a record 57.8% of dry cell weight with a similar growth rate to wild type, thus keeping a high biomass. The neutral lipid content was further increased by 31% under nitrogen-deprivation treatment, still 66% higher than that of wild type. Transgenic microalgae cells exhibited obvious morphological changes, as the cells were shorter and thicker and contained larger oil bodies. Immuno-electron microscopy targeted PtME to the mitochondrion. This study markedly increased the oil content in microalgae, suggesting a new route for developing ideal microalgal strains for industrial biodiesel production.
    Metabolic Engineering 10/2014; 27. DOI:10.1016/j.ymben.2014.10.002 · 6.77 Impact Factor
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    • "These data suggest that NSCs showed different alteration of p53 and cyclin E1 levels in response to a solution containing glucose or pH buffer system or not. The conflict that NSCs exposed to these different harvesting media displayed consistent proliferation inhibition but distinct molecular responses further illustrates that a constrained level of p53 and cyclin E1 is necessary to support normal cell growth [20], [26], [27]. "
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    ABSTRACT: Various solutions are utilized widely for the isolation, harvesting, sorting, testing and transplantation of neural stem cells (NSCs), whereas the effects of harvesting media on the biological characteristics and repair potential of NSCs remain unclear. To examine some of these effects, NSCs were isolated from cortex of E14.5 mice and exposed to the conventional harvesting media [0.9% saline (Saline), phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (ACSF)] or the proliferation culture medium (PCM) for different durations at 4°C. Treated NSCs were grafted by in situ injection into the lesion sites of traumatic brain injury (TBI) mice. In vitro, harvesting media-exposed NSCs displayed time-dependent reduction of viability and proliferation. S phase entry decreased in harvesting media-exposed cells, which was associated with upregulation of p53 protein and downregulation of cyclin E1 protein. Moreover, harvesting media exposure induced the necrosis and apoptosis of NSCs. The levels of Fas-L, cleaved caspase 3 and 8 were increased, which suggests that the death receptor signaling pathway is involved in the apoptosis of NSCs. In addition, exposure to Saline did not facilitate the neuronal differentiation of NSCs, suggesting that Saline exposure may be disadvantageous for neurogenesis. In vivo, NSC-mediated functional recovery in harvesting media-exposed NSC groups was notably attenuated in comparison with the PCM-exposed NSC group. In conclusion, harvesting media exposure modulates the biological characteristics and repair potential of NSCs after TBI. Our results suggest that insight of the effects of harvesting media exposure on NSCs is critical for developing strategies to assure the successful long-term engraftment of NSCs.
    PLoS ONE 09/2014; 9(9):e107865. DOI:10.1371/journal.pone.0107865 · 3.23 Impact Factor
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    • "Moreover, of the three ME isoforms, only ME2 is inhibited by ATP, implying that it may be an energy gauge for cell metabolism (Hsu et al., 2004; Hung et al., 2005; Hsieh et al., 2008). In addition, a recent study showed that suppressing ME2 expression reduced NADPH production and decreased triacylglycerol synthesis more significantly than ME1 depletion (Jiang et al., 2013). Taken together, substantial evidence suggests that the dual cofactor that is characteristic of ME2 may make this enzyme a key switch to meet the metabolic demands of rapidly proliferating cancer cells. "
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    ABSTRACT: Cutaneous melanoma is the most life-threatening neoplasm of the skin, accounting for most skin cancer deaths. Accumulating evidence suggests that targeting metabolism is an appealing strategy for melanoma therapy. Mitochondrial NAD(P)(+)-dependent malic enzyme (ME2), an oxidative decarboxylase, was evaluated for its biological significance in cutaneous melanoma progression. ME2 mRNA and protein expression significantly increased during melanoma progression, as evidenced by Gene Expression Omnibus (GEO) analysis and immunohistochemistry on clinically annotated tissue microarrays, respectively. In addition, ME2 knockdown attenuated melanoma cell proliferation in vitro. ME2 ablation resulted in reduced cellular ATP levels and elevated cellular ROS production, which activated the AMP-activated protein kinase (AMPK) pathway and inhibited acetyl-CoA carboxylase (ACC). Furthermore, ME2 expression was associated to cell migration and invasion. ME2 knockdown decreased anchorage-independent growth in vitro and tumor cell growth in vivo. These results suggested that ME2 might be an important factor in melanoma progression and a novel biomarker of invasion.Journal of Investigative Dermatology accepted article preview online, 09 September 2014. doi:10.1038/jid.2014.385.
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