Regulation of glucose metabolism by p53: Emerging new roles for the tumor suppressor

Madan, Esha; Gogna, Rajan; Bhatt, Madan Lal Brahma; Pati, Uttam; Kuppusamy, Periannan; Mahdi, Abbas Ali

doi:10.18632/oncotarget.389

Cited by 120 publications

(94 citation statements)

References 89 publications

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“…The observation that CHO restriction enhances exerciseinduced p53 signalling is consistent with cell culture data demonstrating a potent effect of glucose deprivation on p53 activity [43]. There is also a growing body of literature demonstrating that training in conditions of reduced CHO availability enhances oxidative adaptations of human skeletal muscle [37,44,45] and, in this regard, the emergence of an AMPK-p53 signalling axis provides an additional pathway that may potentially contribute to this enhanced training effect.…”

Section: Exercise Induces Post-translational Modification Of P53 Andsupporting

confidence: 83%

The Emerging Role of p53 in Exercise Metabolism

Bartlett

Drust

et al. 2013

Sports Med

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The major tumour suppressor protein, p53, is one of the most well-studied proteins in cell biology. Often referred to as the Guardian of the Genome, the list of known functions of p53 include regulatory roles in cell cycle arrest, apoptosis, angiogenesis, DNA repair and cell senescence. More recently, p53 has been implicated as a key molecular player regulating substrate metabolism and exercise-induced mitochondrial biogenesis in skeletal muscle. In this context, the study of p53 therefore has obvious implications for both human health and performance, given that impaired mitochondrial content and function is associated with the pathology of many metabolic disorders such as ageing, type 2 diabetes, obesity and cancer, as well as reduced exercise performance. Studies on p53 knockout (KO) mice collectively demonstrate that ablation of p53 content reduces intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial yield, reduces cytochrome c oxidase (COX) activity and peroxisome proliferator-activated receptor gamma co-activator 1-a protein content whilst also reducing mitochondrial respiration and increasing reactive oxygen species production during state 3 respiration in IMF mitochondria. Additionally, p53 KO mice exhibit marked reductions in exercise capacity (in the magnitude of 50 %) during fatiguing swimming, treadmill running and electrical stimulation protocols. p53 may regulate contractile-induced increases in mitochondrial content via modulating mitochondrial transcription factor A (Tfam) content and/or activity, given that p53 KO mice display reduced skeletal muscle mitochondrial DNA, Tfam messenger RNA and protein levels. Furthermore, upon muscle contraction, p53 is phosphorylated on serine 15 and subsequently translocates to the mitochondria where it forms a complex with Tfam to modulate expression of mitochondrial-encoded subunits of the COX complex. In human skeletal muscle, the exercise-induced phosphorylation of p53 Ser15 is enhanced in conditions of reduced carbohydrate availability in association with enhanced upstream signalling through 5 0 adenosine monophosphateactivated protein kinase but not p38 mitogen-activated protein kinase. In this way, undertaking regular exercise in carbohydrate restricted states may therefore be a practical approach to achieve the physiological benefits of consistent p53 signalling. Although our knowledge of p53 in exercise metabolism has advanced considerably, much of our current understanding of p53 regulation and associated targets is derived from various non-muscle cells and tissues. As such, many fundamental questions remain unanswered in contracting skeletal muscle. Detailed studies concerning the time-course of p53 activation (including additional post-translational modifications and subsequent subcellular translocation), as well as the effects of exercise modality (endurance versus resistance), intensity, duration, fibre type, age, training status and nutrient availability, must now be performed so that we can optimise exercise prescription guideli...

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Section: Exercise Induces Post-translational Modification Of P53 Andsupporting

confidence: 83%

The Emerging Role of p53 in Exercise Metabolism

Bartlett

Drust

et al. 2013

Sports Med

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“…Therefore, the role of TAp73 in neuronal differentiation, as revealed by the TAp73-knockout mouse phenotype, is complex and involves several downstream pathways. The demonstration in this report that GLS2, in addition to miR-34a, is a TAp73 target involved in the differentiation of NB cells, and, in particular, that direct manipulation of GLS2 expression itself modulates NB differentiation, and that Gln deprivation influences the differentiation of cortical neurons in vitro, suggests that the neuronal effects of TAp73 are partly due to its effects on metabolism, since p53 family members, including TAp73, have been reported to have metabolic effects [43][44][45] in addition to regulating Gln metabolism. Despite the fact that TAp73 is not essential for the in vivo regulation of GLS2 expression, our results suggest that TAp73 loss affects glutamate metabolism.…”

Section: Discussionmentioning

confidence: 71%

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Velletri

Romeo²,

Tucci

et al. 2013

Cell Cycle

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The amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). Two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53. Here, we show that the p53 family member TAp73 also drives the expression of GLS2. Specifically, we demonstrate that TAp73 regulates GLS2 during retinoic acid-induced terminal neuronal differentiation of neuroblastoma cells, and overexpression or inhibition of GLS2 modulates neuronal differentiation and intracellular levels of ATP. Moreover, inhibition of GLS activity, by removing Glutamine from the growth medium, impairs in vitro differentiation of cortical neurons. Finally, expression of GLS2 increases during mouse cerebellar development. Although, p73 is dispensable for the in vivo expression of GLS2, TAp73 loss affects GABA and Glutamate levels in cortical neurons. Together, these findings suggest a role for GLS2 acting, at least in part, downstream of p73 in neuronal differentiation and highlight a possible role of p73 in regulating neurotransmitter synthesis

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“…120 The p53 protein is highly conserved in its structure from C. elegans, D. melanogaster to H. sapiens. [121][122][123][124][125][126] While the DBD domain is highly conserved among vertebrates and invertebrates, the C terminus varies, resulting in a change from dimeric structure to a tetramer in the vertebrates. [127][128][129] The more ancient members of the family include p73, involved in cancer, 130 neurodevelopment, 131,132 and aging, 133 and p63, involved in epidermal development, 119,[134][135][136] cancer, [137][138][139][140][141] reproduction, 142 and heart development.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics of the full-length p53 monomer

Chillemi¹,

Davidovich

D’Abramo³

et al. 2013

Cell Cycle

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The p53 protein is frequently mutated in a very large proportion of human tumors, where it seems to acquire gain-of-function activity that facilitates tumor onset and progression. A possible mechanism is the ability of mutant p53 proteins to physically interact with other proteins, including members of the same family, namely p63 and p73, inactivating their function. Assuming that this interaction might occurs at the level of the monomer, to investigate the molecular basis for this interaction, here, we sample the structural flexibility of the wild-type p53 monomeric protein. The results show a strong stability up to 850 ns in the DNA binding domain, with major flexibility in the N-terminal transactivations domains (TAD1 and TAD2) as well as in the C-terminal region (tetramerization domain). Several stable hydrogen bonds have been detected between N-terminal or C-terminal and DNA binding domain, and also between N-terminal and C-terminal. Essential dynamics analysis highlights strongly correlated movements involving TAD1 and the proline-rich region in the N-terminal domain, the tetramerization region in the C-terminal domain; Lys120 in the DNA binding region. The herein presented model is a starting point for further investigation of the whole protein tetramer as well as of its mutants

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Regulation of glucose metabolism by p53: Emerging new roles for the tumor suppressor

Cited by 120 publications

References 89 publications

The Emerging Role of p53 in Exercise Metabolism

The Emerging Role of p53 in Exercise Metabolism

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Molecular dynamics of the full-length p53 monomer

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