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

We found that the treatment with 1 mM butyric acid for 2 days renders Vero cells highly sensitive to ricin-induced apoptosis reflected by cytolysis concomitant with apoptotic cellular and nuclear morphological changes, DNA fragmentation, and increase in caspase-3 like activity, whereas butyric acid alone had no cytotoxic effect on Vero cells. During the treatment with butyric acid, gradual increase in alkaline phosphatase activity, an indicator for butyric acid-induced differentiation, was observed in Vero cells. Although the potency of ricin-mediated protein synthesis was increased in butyric acid-treated Vero cells as compared to untreated cells, the binding and internalization of ricin to the cells were not much affected. Furthermore, DNA fragmentation caused by other protein synthesis inhibitors such as diphtheria toxin and anisomysin were also highly potentiated in butyric acid-treated Vero cells, whereas the potencies of these toxins to inhibit the protein synthesis were not affected by butyric acid treatment. These results suggest that the apoptosis signaling pathway, which may be triggered by cytotoxic stress response caused by toxins, is sensitized in butyric acid-treated cells, while the pathways leading to the protein synthesis inhibition by these toxins are relatively unchanged. No significant differences in the expression levels of p21, p53, and Bcl-2 proteins were observed between butyric acid-treated and untreated Vero cells. The treatment with ricin resulted in the activation of p38 MAP kinase, and this activation occurred on an accelerated time schedule in butyric acid-treated Vero cells than in untreated cells. The specific inhibitor of p38 MAP kinase SB203580 showed a partial inhibitory effect on ricin-induced apoptosis in control Vero cells, but it was less effective in butyric acid-treated Vero cells. Taken together, our results suggest that butyric acid-treatment may result in sensitization of multiple intracellular signal transduction pathways including apoptotic signaling pathways and p38 MAP kinase pathway.
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PMID:Butyric acid sensitizes Vero cells to ricin-induced apoptosis via accelerated activation of multiple signal transduction pathways. 1474 39

ZBP-89 induces apoptosis in human gastrointestinal cancer cells through a p53-independent mechanism. To understand the apoptotic pathway regulated by ZBP-89, we identified downstream signal transduction targets. Ectopic expression of ZBP-89 induced apoptosis through the mitochondrial pathway and was accompanied by activation of all three MAP kinase subfamilies: JNK1/2, ERK1/2 and p38 MAP kinase. ZBP-89-induced apoptosis was markedly enhanced by ERK inhibition with U0126. In contrast, inhibiting JNK with a JNK1-specific peptide inhibitor or dominant-negative JNK2 expression abrogated ZBP-89-mediated apoptosis. The p38 inhibitor SB202190 had no effect on ZBP-89-induced cell death. Protein dephosphorylation assays revealed that ZBP-89 activates JNK via repression of JNK dephosphorylation. Oligonucleotide microarray analyses revealed that ectopic expression of ZBP-89 downregulated expression of the dual-specificity phosphatase MKP6. Overexpression of MKP6 blocked ZBP-89-induced JNK phosphorylation and PARP cleavage. In addition, ectopic expression of ZBP-89 repressed Bcl-xL and Mcl-1 expression, but had no effect on Bcl-2. Silencing ZBP-89 with small interfering RNA enhanced both Bcl-xL and Mcl-1 expression. Taken together, ZBP-89-mediated apoptosis occurs via a p53-independent mechanism that requires JNK activation.
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PMID:ZBP-89-induced apoptosis is p53-independent and requires JNK. 1496 12

The reactive metabolites of benzo[a]pyrene (B[a]P) and cyclopenta[c,d]pyrene (CPP) induced an accumulation/phosphorylation of p53 in Hepa1c1c7 cells, whereas inhibition of p53 reduced the apoptosis. Judged by the inhibiting effect of wortmannin, phosphatidyl-inositol-3 (PI-3) kinases such as DNA-dependent protein kinase (DNA-PK), ATM (ataxia-telangiectasia mutated), and/or ATR (ATM related kinase), appeared to be involved in the DNA damage recognition and the B[a]P-/CPP-induced accumulation of p53. B[a]P and CPP also induced phosphorylation of jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK). While inhibition of JNK had no effects on the B[a]P-/CPP-induced apoptosis, inhibition of p38 MAPK activity reduced this effect. Interestingly, survival signals such as phosphorylation of Akt and Bad seemed to be induced by the B[a]P-/CPP-compounds. Furthermore, also extracellular signal-regulated kinase (ERK)1/2 was activated and seemed to function as a survival signal in B[a]P-/CPP-induced apoptosis.
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PMID:Role of cell signalling involved in induction of apoptosis by benzo[a]pyrene and cyclopenta[c,d]pyrene in Hepa1c1c7 cells. 1544 20

The p53 protein plays a central role in the integration of cellular stress responses. If the cell incurs DNA damage, p53-induced cell cycle arrest is accompanied by p53-facilitated DNA repair. In particular, p53 has been demonstrated to promote both nucleotide excision repair (NER) and base excision repair (BER). Once these repair processes are completed, p53 activity declines and the cell can reenter the cell cycle. A critical mediator of this p53 negative regulatory feedback loop is Mdm2, a p53 transcriptional target whose protein mediates p53 proteolytic degradation. Another such p53 transcriptional target that may function in a p53 negative regulation is the PPM1D phosphatase. PPM1D may inhibit p53 activity through inactivating dephosphorylation of the p38 MAP kinase. We have recently shown that PPM1D suppresses BER in part through dephosphorylation of a key BER effector, the nuclear isoform of uracil DNA glycosylase, or UNG2. This finding further links p53 signaling to DNA repair pathways and illustrates a mechanism by which activated DNA repair systems are returned to a deactivated, homeostatic state.
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PMID:Homeostatic regulation of base excision repair by a p53-induced phosphatase: linking stress response pathways with DNA repair proteins. 1553 43

Activation of the cellular stress pathways (c-Jun N-terminal kinase [JNK] and p38 mitogen-activated protein [MAP] kinase) is linked to apoptosis. However, whether both pathways are required for apoptosis remains unresolved. Hepatitis B virus X protein (pX) activates p38 MAP kinase and JNK pathways and, in response to weak apoptotic signals, sensitizes hepatocytes to apoptosis. Employing hepatocyte cell lines expressing pX, which was regulated by tetracycline, we investigated the mechanism of apoptosis by p38 MAP kinase and JNK pathway activation. Inhibition of the p38 MAP kinase pathway rescues by 80% the initiation of pX-mediated apoptosis, whereas subsequent apoptotic events involve both pathways. pX-mediated activation of p38 MAP kinase and JNK pathways is sustained, inducing the transcription of the death receptor family genes encoding Fas/FasL and tumor necrosis factor receptor 1 (TNFR1)/TNF-alpha and the p53-regulated Bax and Noxa genes. The pX-dependent expression of Fas/FasL and TNFR1/TNF-alpha mediates caspase 8 activation, resulting in Bid cleavage. In turn, activated Bid, acting with pX-induced Bax and Noxa, mediates the mitochondrial release of cytochrome c, resulting in the activation of caspase 9 and apoptosis. Combined antibody neutralization of FasL and TNF-alpha reduces by 70% the initiation of pX-mediated apoptosis. These results support the importance of the pX-dependent activation of both the p38 MAP kinase and JNK pathways in pX-mediated apoptosis and suggest that this mechanism of apoptosis occurs in vivo in response to weak apoptotic signals.
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PMID:Sustained activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase pathways by hepatitis B virus X protein mediates apoptosis via induction of Fas/FasL and tumor necrosis factor (TNF) receptor 1/TNF-alpha expression. 1554 43

Hydroxyurea is commonly used to treat hematologic disorders and some type of solid tumors, but the mechanism for its therapeutic effect is not clearly known. In this study, we examined the effect of hydroxyurea on rat hepatoma McA-RH7777 cells, specifically, on the role of mitogen-activated protein (MAP) kinase signal transduction pathways and p21(Waf1), p27(Kip1) and p53. Rat hepatoma McA-RH7777 cells treated with hydroxyurea for 7 days, caused the inhibition of cell growth in a dose-dependent manner. But, this growth inhibition was not caused by necrosis or apoptosis but instead was associated with cell senescence-like change as evidenced by senescence associated-beta-galactosidase staining, and cells arrest at G1 phase of cell cycle. Phosphorylation of MAP kinases, such as ERK, JNK, and p38, was found to be decreased after treatment of cells with hydroxyurea. But, the expression of p21(Waf1) was increased, while p27(Kip1) and p53 were not detected in hydroxyurea treated rat hepatoma cells. Hydroxyurea treatment induced G1 arrest and a senescence-like changes in rat hepatoma McA-RH7777 cells may be the likely results of signal disruption of MAP kinases (ERK, JNK, and p38 MAP kinase) and p21(Waf1) over-expression.
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PMID:Involvement of mitogen-activated protein kinases and p21Waf1 in hydroxyurea-induced G1 arrest and senescence of McA-RH7777 rat hepatoma cell line. 1555 22

Gastric cancer has been declining for more than half a century, whereas the incidence of oesophageal cancer is increasing rapidly. The histopathological subtype is also changing with a predominance of oesophageal adenocarcinoma compared with squamous carcinoma. The reasons for these epidemiological changes are not clear, although population-based data have implicated gastro-oesophageal reflux disease as a risk factor. In susceptible individuals reflux of duodeno-gastric contents can lead to the development of a columnar-lined oesophagus, commonly called Barrett's oesophagus. This can then progress to adenocarcinoma via a metaplasia-dysplasia-carcinoma sequence. At the current time, the mortality from oesophageal adenocarcinoma exceeds 80% at 5 years. Therefore, endoscopic surveillance programmes have been generally recommended for patients with Barrett's oesophagus in an attempt to detect early, curable lesions. Unfortunately these programmes are cumbersome and costly and have not yet been proved to reduce population mortality. In order to improve patient outcomes we need to be able to identify patients at high risk and to understand the triggers for disease progression. There is mounting evidence that there is an underlying genetic susceptibility to Barrett's oesophagus and oesophageal adenocarcinoma. However, this is likely to be as a result of multiple low penetrance susceptibility genes which have yet to be identified. Once patients are identified as having Barrett's oesophagus their chance for developing adenocarcinoma is in the order of 0.5%-1% per year. The histological assessment of dysplasia as a predictor of cancer development is highly subjective. Therefore multiple, specific somatic mutations in the tissue have been investigated as potential biomarkers. The most promising markers to date are the presence of aneuploidy, loss of heterozygosity of p53 and cyclin D1 overexpression. However, a study of evolutionary relationships suggest that mutations occur in no obligate order. Combinatorial approaches are therefore being advocated which include genomic profiling or the use of a panel of molecular markers in order to define the common molecular signatures that can then be used to predict malignant progression. An alternative approach would be to use markers for the final common pathway following genetic instability, which is the loss of proliferative control. We have demonstrated an increase in the expression of a novel proliferation marker, Mcm2, which occurs during the malignant progression of Barrett's oesophagus. These Mcm2-expressing cells are detectable on the surface, and hence a cytological approach may be applicable. In view of the role of reflux components in the pathogenesis of Barrett's oesophagus the effect of acid and bile on the cell phenotype have been studied. These studies have demonstrated that pulsatile acid and bile exposure induce cell proliferation. The mechanism for the hyperproliferative response appears to involve p38 mitogen activated protein kinase (MAPK) pathways as well as protein kinase C (PKC) and cyclo-oxygenases. A clinical implication of the laboratory studies is that suppression of acid and bile may need to be profound in order to suppress cell proliferation and, by inference, ultimately prevent the development of dysplasia. There is some support for this concept from short-term clinical studies, and a large randomised chemoprevention trial is being instigated which will evaluate the effect of proton pump inhibitors with or without aspirin. Given the epidemic increase in oesophageal adenocarcinoma and the dismal 5-year mortality rate, a radical approach is necessary to prevent cancer development in individuals with pre-malignant lesions.
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PMID:Genetics and prevention of oesophageal adenocarcinoma. 1564 81

n-3 polyunsaturated fatty acids (PUFAs) have been shown to exert beneficial effects in the prevention of cardiovascular disease, inflammation, and on tumor growth. To investigate effects of PUFAs on proliferation and apoptosis in endothelial cells, we tested the n-3 PUFA docosahexaenoic acid (DHA) and the n-6 PUFA arachidonic acid (AA) in human umbilical vein endothelial cells (HUVEC). The mitochondrial membrane potential (MMP) and the production of reactive oxygen species were examined by flow cytometry. Phosphorylation of p53 or p38 MAP kinase, and total levels of p53 were measured by Western blot. DNA binding activity of p53 was analyzed with a TransAM transcription factor assay kit. Tube formation was assessed on Matrigel. In proliferating HUVEC, but not in confluent cells, DHA reduced cell viability and induced apoptosis, as demonstrated by increases in membrane leakage (propidium iodide (PI) staining), Annexin-V binding, sub G(1) phase in the cell cycle, and TUNEL-positive cells. AA had no effect on these parameters. In addition to a reduced MMP and increased reactive oxygen species, phosphorylation of p38 and p53 (serine 15) and impaired DNA binding of p53 were observed. There was no change in total levels of p53. The p38 inhibitor SB203580 had no effect on Annexin V binding. DHA also attenuated HUVEC tube formation. Taken together, DHA induces apoptosis in proliferating, but not in resting HUVEC, potentially via the phosphorylation of p53, resulting in decreased p53 DNA binding. The results suggest that anti-angiogenic effects of DHA may be due to induction of apoptosis in proliferating endothelial cells.
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PMID:Docosahexaenoic acid induces apoptosis in proliferating human endothelial cells. 1579 39

The p53 pathway responds to stresses that can disrupt the fidelity of DNA replication and cell division. A stress signal is transmitted to the p53 protein by post-translational modifications. This results in the activation of the p53 protein as a transcription factor that initiates a program of cell cycle arrest, cellular senescence or apoptosis. The transcriptional network of p53-responsive genes produces proteins that interact with a large number of other signal transduction pathways in the cell and a number of positive and negative autoregulatory feedback loops act upon the p53 response. There are at least seven negative and three positive feedback loops described here, and of these, six act through the MDM-2 protein to regulate p53 activity. The p53 circuit communicates with the Wnt-beta-catenin, IGF-1-AKT, Rb-E2F, p38 MAP kinase, cyclin-cdk, p14/19 ARF pathways and the cyclin G-PP2A, and p73 gene products. There are at least three different ubiquitin ligases that can regulate p53 in an autoregulatory manner: MDM-2, Cop-1 and Pirh-2. The meaning of this redundancy and the relative activity of each of these feedback loops in different cell types or stages of development remains to be elucidated. The interconnections between signal transduction pathways will play a central role in our understanding of cancer.
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PMID:The p53 pathway: positive and negative feedback loops. 1583 23

p73, a homologue to the tumor suppressor gene p53, is involved in tumorigenesis, though its specific role remains unclear. The gene has two distinct promoters which allow the formation of two protein isoforms with opposite effects: full-length transactivating (TA) p73 shows pro-apoptotic effects, while the shorter DeltaNp73, which lacks the N-terminal transactivating domain, has an evident anti-apoptotic function. Unlike p53, the p73 gene is rarely mutated in human cancers. However, alterations in the relative levels of TA and DeltaNp73 have been shown to correlate with prognosis in several human cancers, suggesting that the fine regulation of these two isoforms is of pivotal importance in controlling proliferation and cell death. Much effort is currently focused on the elucidation of the mechanisms that differentially control TA and DeltaNp73 activity and protein stability, a process complicated by the finding that both proteins are regulated by a similar suite of complex post-translational modifications that include ubiquitination, sequential phosphorylation, prolyl-isomerization, recruitment into the PML-nuclear body (PML-NB), and acetylation. Here we shall consider the main regulatory partners of p73, with particular attention to the recently discovered Itch- and Nedd8-mediated degradation pathways, along with the emerging roles of PML, p38 MAP kinase, Pin1, and p300 in p73 transcriptional activation, and possible mechanisms for the differential regulation of the TAp73 and DeltaNp73 isoforms.
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PMID:Regulation of the p73 protein stability and degradation. 1586 26


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