Metabolic pathways regulated by TAp73 in response to oxidative stress

Abstract

Reactive oxygen species are involved in both physiological and pathological processes including neurodegeneration and cancer. Therefore, cells have developed scavenging mechanisms to maintain redox homeostasis under control. Tumor suppressor genes play a critical role in the regulation of antioxidant genes. Here, we investigated whether the tumor suppressor gene TAp73 is involved in the regulation of metabolic adaptations triggered in response to oxidative stress. H2O2 treatment resulted in numerous biochemical changes in both control and TAp73 knockout (TAp73−/−) mouse embryonic fibroblasts, however the extent of these changes was more pronounced in TAp73−/− cells when compared to control cells. In particular, loss of TAp73 led to alterations in glucose, nucleotide and amino acid metabolism. In addition, H2O2 treatment resulted in increased pentose phosphate pathway (PPP) activity in null mouse embryonic fibroblasts. Overall, our results suggest that in the absence of TAp73, H2O2 treatment results in an enhanced oxidative environment, and at the same time in an increased pro-anabolic phenotype. In conclusion, the metabolic profile observed reinforces the role of TAp73 as tumor suppressor and indicates that TAp73 exerts this function, at least partially, by regulation of cellular metabolism.

TAp73 is a marker of glutamine addiction in medulloblastoma

“…Numerous evidence suggests that p73 has a well-defined role in cell metabolism and brain development (Agostini et al 2016). However, because of the existence of numerous splice variants as well as the regulation of protein stability by proteasomal degradation and micro-RNA, its precise effect on cellular metabolism is currently ill defined.…”

Mitochondrial dynamics in the regulation of neurogenesis: From development to the adult brain

“…The differentiation of stem cells to a specific lineage is accompanied by a metabolic switch and activation of mitochondrial respiration resulting in the shift from glycolysis to OXPHOS as the predominant energy source (Mandal et al, 2011;Shyh-Chang et al, 2013;Takubo et al, 2013). Similarly, in vivo, in vitro, and single-cell transcriptomic studies have established that a metabolic shift also occurs during neurogenesis, whereby NSCs display a glycolytic metabolism while postmitotic neurons are heavily reliant an OXPHOS (Llorens-Bobadilla et al, 2015;Shin et al, 2015;Agostini et al, 2016;Khacho et al, 2016;Beckervordersandforth et al, 2017b). The metabolic switch during neuronal differentiation is mediated through coordinated modification in the expression of metabolic regulators.…”

p73 Regulates Primary Cortical Neuron Metabolism: a Global Metabolic Profile

“…Recently we have also shown that p73 regulates cellular metabolism [37,15,18]. With regard to CNS, our previous data indicate that cortical neurons isolated from TAp73-/-mice appeared to have reduced levels of GABA, while levels of the inhibitory neurotransmitter glycine were reduced in ΔNp73-/-cells [41].…”

“…Samples were extracted and prepared for analysis using Metabolon's standard solvent extraction method (Metabolon, Inc. NC, USA). The sample preparation process was carried out as previously described [15]. Briefly, the protein fraction was removed by using a proprietary series of organic and aqueous extraction solutions.…”

“…The transcription factor p73 [1-3], a member of the p53-family [4-6], [7,8] exerts its role through the regulation of several biological processes including cell survival [9][10][11], differentiation [12][13][14], cellular metabolism [15][16][17][18][19][20], and autophagy [21]. This pleiotropic role of p73 is mainly due to the fact that the tp73 gene is expressed in numerous isoforms, including two main Nterminal isoforms: a full-length protein named TAp73, and a shorter, N-terminal truncated ΔNp73 isoform.…”