Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role that the p53 tumor suppressor gene product plays in cellular differentiation remains controversial. However, recent evidence indicates that p53 is required for proper embryogenesis. We have studied the effect of p53 on the expression mediated by the promoter of the rat muscle-specific phosphoglycerate mutase gene (M-PGAM), a marker for cardiac and skeletal muscle differentiation. Experiments involving transient transfection, mobility shift assay, and site-directed mutagenesis demonstrated that p53 specifically binds and transactivates the M-PGAM promoter. The p53-related proteins p51A and p73L also transactivated M-PGAM. Moreover, stable expression of a p53 dominant mutant in C2C12 cells blocked the induction of M-PGAM expression during the myoblast to myotube transition and the ability of p53, p51A, and p73L to transactivate the M-PGAM promoter. In addition, impaired expression of M-PGAM was observed in a subset of p53-null animals in heart and muscle tissues of anterior-ventral location. These results demonstrate that p53 is a transcriptional activator of M-PGAM that contributes in vivo to the control of its cardiac expression. These data support previous findings indicating a role for p53 in cellular differentiation.
 ...
PMID:p53 is a transcriptional activator of the muscle-specific phosphoglycerate mutase gene and contributes in vivo to the control of its cardiac expression. 1035 11

An unbiased screen for genes that can immortalize mouse embryonic fibroblasts identified the glycolytic enzyme phosphoglycerate mutase (PGM). A 2-fold increase in PGM activity enhances glycolytic flux, allows indefinite proliferation, and renders cells resistant to ras-induced arrest. Glucosephosphate isomerase, another glycolytic enzyme, displays similar activity and, conversely, depletion of PGM or glucosephosphate isomerase with short interfering RNA triggers premature senescence. Immortalized mouse embryonic fibroblasts and mouse embryonic stem cells display higher glycolytic flux and more resistance to oxidative damage than senescent cells. Because wild-type p53 down-regulates PGM, mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis.
 ...
PMID:Glycolytic enzymes can modulate cellular life span. 1566 93

Reactive oxygen species (ROS) play a crucial role not only in the physiological signal transduction but also in the pathogenesis of several human diseases such as atherosclerosis, neuro-degenerative diseases, metabolic disorders, aging or cancer amongst others. Oxidative stress is also responsible for cellular and organism senescence, in accordance with what Harman initially proposed in the free radical theory of aging. Recent findings support the notion that protection from oxidative stress can increase life span significantly. We reported that enhanced glycolysis could modulate cellular life span with reduction of oxidative stress. Moreover, the tumor suppressor gene p53 controls post-transcriptionally the level of the glycolytic enzyme, phosphoglycerate mutase (PGM). As enhanced glycolysis is a distinctive and prominent feature of cancer cells (termed the Warburg effect), our findings disclosed a novel aspect of the Warburg effect: the connection between senescence and oxidative stress.
 ...
PMID:Protection from oxidative stress by enhanced glycolysis; a possible mechanism of cellular immortalization. 1712 14

The function of p53 as a tumor suppressor remains undisputed. p53 has a central role in cellular stress responses as well as affecting cancer development and progression. The word "central", however, is becoming increasingly more of an understatement as the list of p53-regulated pathways and processes is ever expanding. Although much focus continues to center on p53-mediated signaling cascades that control cell growth arrest and/or apoptosis, recent work has begun to define a role for p53 in the regulation of metabolic pathways typically thought of as essential for maintaining life. With the first potential link between p53 and glycolysis reported nearly ten years ago, the topic has gained a renewed interest. Recent studies now demonstrate the ability of p53 to regulate the expression of several novel genes including PGM (phosphoglycerate mutase), TIGAR (TP53-induced glycolysis and apoptosis regulator) and, SCO2 (synthesis of cytochrome c oxidase 2), each intimately linked to the processes of glycolysis and oxidative phosphorylation. With this discovery, yet another novel means by which p53 carries out its tumor suppressor function is brought into light.
 ...
PMID:The regulation of energy generating metabolic pathways by p53. 1720 63

The histidine phosphatase superfamily is a large functionally diverse group of proteins. They share a conserved catalytic core centred on a histidine which becomes phosphorylated during the course of the reaction. Although the superfamily is overwhelmingly composed of phosphatases, the earliest known and arguably best-studied member is dPGM (cofactor-dependent phosphoglycerate mutase). The superfamily contains two branches sharing very limited sequence similarity: the first containing dPGM, fructose-2,6-bisphosphatase, PhoE, SixA, TIGAR [TP53 (tumour protein 53)-induced glycolysis and apoptosis regulator], Sts-1 and many other activities, and the second, smaller, branch composed mainly of acid phosphatases and phytases. Human representatives of both branches are of considerable medical interest, and various parasites contain superfamily members whose inhibition might have therapeutic value. Additionally, several phosphatases, notably the phytases, have current or potential applications in agriculture. The present review aims to draw together what is known about structure and function in the superfamily. With the benefit of an expanding set of histidine phosphatase superfamily structures, a clearer picture of the conserved elements is obtained, along with, conversely, a view of the sometimes surprising variation in substrate-binding and proton donor residues across the superfamily. This analysis should contribute to correcting a history of over- and mis-annotation in the superfamily, but also suggests that structural knowledge, from models or experimental structures, in conjunction with experimental assays, will prove vital for the future description of function in the superfamily.
 ...
PMID:The histidine phosphatase superfamily: structure and function. 1809 46

Metabolic alteration in cancer cells is one of the most conspicuous characteristics that distinguish cancer cells from normal cells. Many studies suggest that several underlying mechanisms lead to the Warburg effect (increased aerobic glycolysis) during cancer development. Here, we explored how oroxylin A affected the glycolytic metabolism in cancer cells and the underlying mechanism involved in this process. Our data revealed that both oroxylin A and adriamycin could inhibit lactate generation and glucose uptake in HepG2 cells at mild concentrations, without causing robust cell apoptosis. Oroxylin A has exerted little influence on the oxygen consumption, whereas adriamycin decreased oxygen consumption in a concentration-dependent manner. Moreover, oroxylin A could increase protein and mRNA expression of TP53-induced glycolysis and apoptosis regulator (TIGAR) and synthesis of cytochrome c oxidase 2 (SCO2), which are the key metabolic modulators regulated by p53. Meanwhile adriamycin could increase protein and mRNA expression of TIGAR and SCO2, but decrease that of phosphoglycerate mutase (PGM). Oroxylin A and adriamycin also modulated the stability and activity of p53 through inducing phosphorylation of p53 at Ser15 and suppressing the expression of MDM2. Furthermore, p53 siRNA and p53 inhibitor assay in wild-type p53 HepG2 cells both revealed the key role of p53 in oroxylin A and adriamycin-mediated glycolytic metabolism regulation. Transfecting wt p53 plasmid to p53-deficient H1299 cells could inverse some of the metabolic characteristics regulated by oroxylin A. This study revealed a new aspect of glucose metabolism regulation of oroxylin A, which may contribute to its new anticancer mechanism.
 ...
PMID:Two p53-related metabolic regulators, TIGAR and SCO2, contribute to oroxylin A-mediated glucose metabolism in human hepatoma HepG2 cells. 2361 20

Identification of driver mutations in lung adenocarcinoma has led to development of targeted agents that are already approved for clinical use or are in clinical trials. Therefore, the number of biomarkers that will be needed to assess is expected to rapidly increase. This calls for the implementation of methods probing the mutational status of multiple genes for inoperable cases, for which limited cytological or bioptic material is available. Cytology specimens from 38 lung adenocarcinomas were subjected to the simultaneous assessment of 504 mutational hotspots of 22 lung cancer-associated genes using 10 nanograms of DNA and Ion Torrent PGM next-generation sequencing. Thirty-six cases were successfully sequenced (95%). In 24/36 cases (67%) at least one mutated gene was observed, including EGFR, KRAS, PIK3CA, BRAF, TP53, PTEN, MET, SMAD4, FGFR3, STK11, MAP2K1. EGFR and KRAS mutations, respectively found in 6/36 (16%) and 10/36 (28%) cases, were mutually exclusive. Nine samples (25%) showed concurrent alterations in different genes. The next-generation sequencing test used is superior to current standard methodologies, as it interrogates multiple genes and requires limited amounts of DNA. Its applicability to routine cytology samples might allow a significant increase in the fraction of lung cancer patients eligible for personalized therapy.
...
PMID:Molecular typing of lung adenocarcinoma on cytological samples using a multigene next generation sequencing panel. 2423 84

Despite the well-documented clinical significance of the Warburg effect, it remains unclear how the aggressive glycolytic rates of tumor cells might contribute to other hallmarks of cancer, such as bypass of senescence. Here, we report that, during oncogene- or DNA damage-induced senescence, Pak1-mediated phosphorylation of phosphoglycerate mutase (PGAM) predisposes the glycolytic enzyme to ubiquitin-mediated degradation. We identify Mdm2 as a direct binding partner and ubiquitin ligase for PGAM in cultured cells and in vitro. Mutations in PGAM and Mdm2 that abrogate ubiquitination of PGAM restored the proliferative potential of primary cells under stress conditions and promoted neoplastic transformation. We propose that Mdm2, a downstream effector of p53, attenuates the Warburg effect via ubiquitination and degradation of PGAM.
...
PMID:Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2. 2456 57

Enhanced glycolysis in cancer, called the Warburg effect, is a well-known feature of cancer metabolism. Recent advances revealed that the Warburg effect is coupled to many other cancer properties, including adaptation to hypoxia and low nutrients, immortalisation, resistance to oxidative stress and apoptotic stimuli, and elevated biomass synthesis. These linkages are mediated by various oncogenic molecules and signals, such as c-Myc, p53, and the insulin/Ras pathway. Furthermore, several regulators of glycolysis have been recently identified as oncogene candidates, including the hypoxia-inducible factor pathway, sirtuins, adenosine monophosphate-activated kinase, glycolytic pyruvate kinase M2, phosphoglycerate mutase, and oncometabolites. The interplay between glycolysis and oncogenic events will be the focus of this review.
 ...
PMID:Dysregulated glycolysis as an oncogenic event. 2560 64

Exhaled breath condensate (EBC) is a non-invasive source that can be used for studying different genetic alterations occurring in lung tissue. However, the low yield of DNA available from EBC has hampered the more detailed mutation analysis by conventional methods. We applied the more sensitive amplicon-based next generation sequencing (NGS) to identify cancer related mutations in DNA isolated from EBC. In order to apply any method for the purpose of mutation screening in cancer patients, it is important to clarify the incidence of these mutations in healthy individuals. Therefore, we studied mutations in hotspot regions of 22 cancer genes of 20 healthy, mainly non-smoker individuals, using AmpliSeq colon and lung cancer panel and sequenced on Ion PGM.In 15 individuals, we detected 35 missense mutations in TP53, KRAS, NRAS, SMAD4, MET, CTNNB1, PTEN, BRAF, DDR2, EGFR, PIK3CA, NOTCH1, FBXW7, FGFR3, and ERBB2: these have been earlier reported in different tumor tissues. Additionally, 106 novel mutations not reported previously were also detected. One healthy non-smoker subject had a KRAS G12D mutation in EBC DNA.Our results demonstrate that DNA from EBC of healthy subjects can reveal mutations that could represent very early neoplastic changes or alternatively a normal process of apoptosis eliminating damaged cells with mutations or altered genetic material. Further assessment is needed to determine if NGS analysis of EBC could be a screening method for high risk individuals such as smokers, where it could be applied in the early diagnosis of lung cancer and monitoring treatment efficacy.
 ...
PMID:Presence of cancer-associated mutations in exhaled breath condensates of healthy individuals by next generation sequencing. 2819 89


1 2 Next >>