A nucleocytoplasmic malate dehydrogenase regulates p53 transcriptional activity in response to metabolic stress

Abstract

Metabolic enzymes have been shown to function as transcriptional regulators. p53, a tumor-suppressive transcription factor, was recently found to regulate energy metabolism. These combined facts raise the possibility that metabolic enzymes may directly regulate p53 function. Here, we discover that nucleocytoplasmic malate dehydrogenase-1 (MDH1) physically associates with p53. Upon glucose deprivation, MDH1 stabilizes and transactivates p53 by binding to p53-responsive elements in the promoter of downstream genes. Knockdown of MDH1 significantly reduces binding of acetylated-p53 and transcription-active histone codes to the promoter upon glucose depletion. MDH1 regulates p53-dependent cell-cycle arrest and apoptosis in response to glucose deprivation, suggesting that MDH1 functions as a transcriptional regulator for a p53-dependent metabolic checkpoint. Our findings provide insight into how metabolism is directly linked to gene expression for controlling cellular events in response to metabolic stress. Two fundamental processes-energy metabolism and gene regulation-in living organisms are considered indirectly linked to each other due to their different functional locations. Recent findings that some metabolic enzymes function as transcriptional regulators have implicated direct coupling of energy metabolism with gene regulation. [1][2][3] For instance, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serves as a co-activator to regulate the expression of histone H2B. 4 Nuclear GAPDH also activates p300/CBP and induces apoptotic genes. 5 In addition, Arg5/6, a yeast metabolic enzyme involved in arginine biosynthesis, regulates the transcription of nuclear and mitochondrial target genes, 6 and plant hexokinase 1 forms a nuclear glucose signaling complex core that directly modulates specific target gene transcription. 7 Glucose is the central molecule for energy metabolism in glycolysis and in the tricarboxylic acid (TCA) cycle and mitochondrial respiration. Interestingly, cancer cells have long been known to have altered glucose metabolism by preferentially acquiring energy from glycolysis rather than from mitochondrial respiration. 8 This metabolic shift to aerobic glycolysis in cancer cells is commonly referred to as the Warburg effect. 9,10 Recently, pyruvate kinase M2 isoform was found to be important for aerobic glycolysis and cancer metabolism. 11 But the molecular mechanism underlying the Warburg effect is still unclear. Because tumor formation is basically caused by dysregulation of gene expression by a genetic or epigenetic alteration, the Warburg effect may be caused by dysregulated transcription.p53 is the best-known transcription factor that controls cell-cycle arrest and cell death in response to a wide range of stresses. 12,13 However, the tumor-suppressive function of p53 has been mainly studied under conditions of DNA damage with g-irradiation, UV and free radicals. Intriguingly, recent findings that p53 regulates glucose metabolism have invoked vigorous interest in the direct linkage between metab...

Rôle du suppresseur de tumeurs p53 dans le contrôle du métabolisme

“…HDAC : histone déacétylase ; SIRT : sirtuin ; HAT : histone acétyltransférase ; ATM : ataxia telangiectasia mutated ; ATR : ATM and Rad3-related ; AMPK : AMP-kinase ; PGC1 : peroxisome proliferator-activated receptor  coactivator 1. De façon intéressante, certaines enzymes du métabo-lisme (notamment la malate déhydrogénase 1) semblent capables de moduler directement les activités transactivatrices de p53 en réponse à une carence en glucose [28]. À l'inverse, la perturbation d'autres enzymes du métabolisme, telles que les enzymes maliques ME1 et -2, induit l'activation de p53 par deux mécanismes distincts, impliquant respectivement la modulation de l'expression de MDM2 et l'activation de l'AMPK [29].…”

Identification and Biochemical Characterization of a Thermostable Malate Dehydrogenase from the MesophileStreptomyces coelicolorA3(2)

“…17,18) MDH is a widespread enzyme widely distributed throughout the three domains of life. 1,5) Although it has been isolated and studied extensively from many diverse sources, information on bacterial MDHs is scarce, and biochemical analyses of them are not yet as well known as eukaryotic MDHs. Streptomyces (multicellular prokaryotes) are Gram-positive soil bacteria that carry out complex morphological differentiation in the formation of filamentous mycelium like fungi (eukaryotes), an example of convergent evolution caused by adaptation to similar ecological niches.…”

“…1,2) It plays crucial roles in many metabolic pathways, including the tricarboxylic acid cycle, amino acid synthesis, gluconeogenesis, maintenance of the oxidation/reduction balance, and metabolic stress. [3][4][5] For example, in the case of the malateaspartate shuttle, involved in gluconeogenesis, the mitochondrial MDH (mMDH) and the cytosolic MDH (cMDH) are required for good balance of the NAD/ NADH ratio between the mitochondrial and cytosolic pools.…”

Alteration of coenzyme specificity of malate dehydrogenase from Streptomyces coelicolor A3(2) by site-directed mutagenesis

“…It plays crucial roles in many metabolic pathways, including the tricarboxylic acid cycle, amino acid synthesis, gluconeogenesis, maintenance of the oxidation/reduction balance and metabolic stress (Goward and Nicholls, 1994;Lee et al, 2009;Liu et al, 2013;Menckhoff et al, 2013).…”

“…MDH can be divided into NAD + -dependent MDH (NAD-MDH) (EC 1.1.1.37) and NADP + -dependent MDH (NADP-MDH) (EC 1.1.1.82) (Lee et al, 2009), according to preference for cofactors. Most bacterial and archaeal MDHs are NAD-MDH.…”