Whereas cell cycle arrest, apoptosis, and senescence are traditionally thought of as the major functions of the tumor suppressor p53, recent studies revealed two unique functions for this protein: p53 regulates cellular energy metabolism and antioxidant defense mechanisms. Here, we identify glutaminase 2 (GLS2) as a previously uncharacterized p53 target gene to mediate these two functions of the p53 protein. GLS2 encodes a mitochondrial glutaminase catalyzing the hydrolysis of glutamine to glutamate. p53 increases the GLS2 expression under both nonstressed and stressed conditions. GLS2 regulates cellular energy metabolism by increasing production of glutamate and α-ketoglutarate, which in turn results in enhanced mitochondrial respiration and ATP generation. Furthermore, GLS2 regulates antioxidant defense function in cells by increasing reduced glutathione (GSH) levels and decreasing ROS levels, which in turn protects cells from oxidative stress (e.g., H 2 O 2 )-induced apoptosis. Consistent with these functions of GLS2, the activation of p53 increases the levels of glutamate and α-ketoglutarate, mitochondrial respiration rate, and GSH levels and decreases reactive oxygen species (ROS) levels in cells. Furthermore, GLS2 expression is lost or greatly decreased in hepatocellular carcinomas and the overexpression of GLS2 greatly reduced tumor cell colony formation. These results demonstrated that as a unique p53 target gene, GLS2 is a mediator of p53's role in energy metabolism and antioxidant defense, which can contribute to its role in tumor suppression.reactive oxygen species | oxidative phosphorylation p 53 mainly exerts its tumor suppression function through the transcriptional regulation of its target genes. In response to stress, p53 selectively regulates the expression of its target genes, which results in cell cycle arrest, apoptosis, or senescence (1, 2). Whereas these responses are traditionally thought of as the major functions of p53 in tumor prevention, recent studies revealed two unique functions for this protein: p53 regulates cellular energy metabolism and antioxidant defense mechanisms. Emerging evidence has shown that these two functions of p53 contribute greatly to p53's role in tumor suppression (3-5).The recent identification of SCO2 and TIGAR as two p53 target genes revealed a unique function of p53 in the regulation of energy metabolism and ATP generation pathways (3, 4). The SCO2 gene is a key regulator of the cytochrome c oxidase complex that is essential for mitochondrial respiration. TIGAR functions to lower fructose-2, 6,-bisphosphate levels and thus slows glycolysis and directs glucose to the pentose phosphate pathway. p53 induces SCO2 expression to enhance mitochondrial respiration and induces TIGAR expression to slow glycolysis. Loss of p53 results in decreased oxygen consumption and impaired mitochondrial respiration and promotes a switch to high glucose utilization in aerobic glycolysis in cells. In mice, p53 loss results in reduced endurance during physical exercise, suggesting a ...

Tumour cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Its mechanism is not well understood. The tumour suppressor gene p53 is frequently mutated in tumours. Many tumour-associated mutant p53 (mutp53) proteins not only lose tumour suppressive function but also gain new oncogenic functions that are independent of wild-type p53, defined as mutp53 gain of function (GOF). Here we show that tumour-associated mutp53 stimulates the Warburg effect in cultured cells and mutp53 knockin mice as a new mutp53 GOF. Mutp53 stimulates the Warburg effect through promoting GLUT1 translocation to the plasma membrane, which is mediated by activated RhoA and its downstream effector ROCK. Inhibition of RhoA/ROCK/GLUT1 signalling largely abolishes mutp53 GOF in stimulating the Warburg effect. Furthermore, inhibition of glycolysis in tumour cells greatly compromises mutp53 GOF in promoting tumorigenesis. Thus, our results reveal a new mutp53 GOF and a mechanism for controlling the Warburg effect.

Regulation of energy metabolism is a novel function of p53 in tumor suppression. Parkin (PARK2), a Parkinson disease-associated gene, is a potential tumor suppressor whose expression is frequently diminished in tumors. Here Parkin was identified as a p53 target gene that is an important mediator of p53's function in regulating energy metabolism. The human and mouse Parkin genes contain functional p53 responsive elements, and p53 increases the transcription of Parkin in both humans and mice. Parkin contributes to the function of p53 in glucose metabolism; Parkin deficiency activates glycolysis and reduces mitochondrial respiration, leading to the Warburg effect. Restoration of Parkin expression reverses the Warburg effect in cells. Thus, Parkin deficiency is a novel mechanism for the Warburg effect in tumors. Parkin also contributes to the function of p53 in antioxidant defense. Furthermore, Parkin deficiency sensitizes mice to γ-irradiation-induced tumorigenesis, which provides further direct evidence to support a role of Parkin in tumor suppression. Our results suggest that as a novel component in the p53 pathway, Parkin contributes to the functions of p53 in regulating energy metabolism, especially the Warburg effect, and antioxidant defense, and thus the function of p53 in tumor suppression. Metabolic alterations are a hallmark of tumor cells (1, 2). Whereas normal cells use mitochondrial respiration to provide energy, the majority of tumor cells preferentially use aerobic glycolysis, a switch known as the Warburg effect (3). Because glycolysis produces ATP much less efficiently than mitochondrial respiration, tumor cells compensate by having a much higher rate of glucose uptake and utilization than normal cells (1, 2). Recent studies have strongly suggested that the Warburg effect is a key contributor to malignant progression (1, 2), and reversing the Warburg effect inhibits the tumorigenicity of cancer cells (4, 5). However, the underlying mechanisms for the Warburg effect are not well-understood (1, 2).p53 plays a central role in tumor prevention. As a transcription factor, in response to stress, p53 transcribes its target genes to start various cellular responses, including cell-cycle arrest, apoptosis, and/or senescence, to prevent tumor formation (6, 7). Recent studies have revealed that regulating energy metabolism and the Warburg effect is a novel function of p53 in tumor suppression (2, 8). p53 induces TIGAR (TP53-induced glycolysis and apoptosis regulator) to reduce glycolysis (9), and induces SCO2 (10) and GLS2 (11, 12) to promote mitochondrial respiration. Loss of p53 results in decreased mitochondrial respiration and enhanced glycolysis, leading to the Warburg effect. Furthermore, regulating antioxidant defense has recently been revealed as another novel function for p53 (8, 13). p53 induces several antioxidant genes, including Sestrins (14), TIGAR (9), ALDH4 (15), and GLS2 (11, 12), to reduce the levels of reactive oxygen species (ROS) and DNA damage in cells, which contributes greatly to the ro...

We present a novel framework for carrying out global analyses of the Standard Model Effective Field Theory (SMEFT) at dimension-six: SMEFiT. This approach is based on the Monte Carlo replica method for deriving a faithful estimate of the experimental and theoretical uncertainties and enables one to construct the probability distribution in the space of the SMEFT degrees of freedom. As a proof of concept of the SMEFiT methodology, we present a first study of the constraints on the SMEFT provided by top quark production measurements from the LHC. Our analysis includes more than 30 independent measurements from 10 different processes at √ s = 8 and 13 TeV such as inclusive tt and single-top production and the associated production of top quarks with weak vector bosons and the Higgs boson. State-of-the-art theoretical calculations are adopted both for the Standard Model and for the SMEFT contributions, where in the latter case NLO QCD corrections are included for the majority of processes. We derive bounds for the 34 degrees of freedom relevant for the interpretation of the LHC top quark data and compare these bounds with previously reported constraints. Our study illustrates the significant potential of LHC precision measurements to constrain physics beyond the Standard Model in a model-independent way, and paves the way towards a global analysis of the SMEFT.