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)

To elucidate whether nitric oxide secreted from irradiated cells affects cellular radiosensitivity, we examined the accumulation of inducible nitric oxide synthase, TP53 and HSP72, the concentration of nitrite in the medium of cells after X irradiation, and cellular radiosensitivity using two human glioblastoma cell lines, A-172, which has a wild-type TP53 gene, and a transfectant of A-172 cells, A-172/mp53, bearing a mutated TP53 gene. Accumulation of inducible nitric oxide synthase was caused by X irradiation of the mutant TP53 cells but not of the wild-type TP53 cells. Accumulation of TP53 and HSP72 in the wild-type TP53 cells was observed by cocultivation with irradiated mutant TP53 cells, and the accumulation was abolished by the addition of an inhibitor for inducible nitric oxide synthase, aminoguanidine, to the medium. Likewise, accumulation of these proteins was observed in the wild-type TP53 cells after exposure to conditioned medium from irradiated mutant TP53 cells, and the accumulation was abolished by the addition of a specific nitric oxide scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, to the medium. The radiosensitivity of wild-type TP53 cells was reduced when the cells were cultured in conditioned medium from irradiated mutant TP53 cells compared to conventional fresh growth medium. Collectively, these findings indicate the potential importance of an intercellular signal transduction pathway initiated by nitric oxide in the cellular response to ionizing radiation.
 ...
PMID:Induction of radioresistance by a nitric oxide-mediated bystander effect. 1118 88

Over 15,000 human tumor p53 mutations have been recorded in the scientific literature, including over 700 mutations in esophageal tumors. There are no data on p53 mutations in esophageal cancer patients from Iran yet; however, this country experiences one of the highest cancer mortality rates in the world for esophageal squamous cell carcinomas (ESCCs). The causes of this high cancer burden in Iran remain obscure and do not appear to be related to tobacco and alcohol consumption, the two major risk factors identified in Europe and North America. Because molecular analysis of tumors can provide clues to endogenous or environmental factors contributing to high cancer risk, we examined 74 Iranian ESCCs for the presence of mutations in exons 5-8 of the p53 gene by PCR and direct sequencing. Forty-eight of the 74 tumors (65%) had one or more p53 gene point mutations, including 5 patients with two or more mutations and one with a tandem mutation in codon 242. Surprisingly, over one-third of the 54 mutations we identified were transitions at CpG sites (20 of a total of 54 mutations, or 37%), a class of mutation that is significantly less common (16% of mutations) in the compilation of ESCC mutations from other countries (chi2 statistic, P < 0.0002), whereas transversions, which the literature shows to be common in ESCCs from non-Iranian patients, were infrequent in the tumors we examined here. Elevated levels of cyclooxygenase-2 and inducible nitric oxide synthase were observed in 74 and 91%, respectively, of tumors from Tehran as determined by immunohistochemistry, and high COX-2 expression correlated significantly with the presence of a p53 mutation in the tumor. Mediators of the inflammatory response in esophageal mucosa, perhaps in conjunction with specific dietary or cultural practices in Iran, may contribute importantly to the p53 mutation load in Iranian ESCC patients.
 ...
PMID:Unusual profile and high prevalence of p53 mutations in esophageal squamous cell carcinomas from northern Iran. 1130 96

Acute myelogenous leukemia (AML) can be separated by whether the presentation was proceeded by a myelodysplastic (MDS related AML) or developed de novo (dAML). Clinically, MDS related AML (mAML) has been considered to have a worse prognosis that dAML. The objective of this literature review was to identify unique biologic features of mAML. Compared to dAML, mAML is characterized by an altered immunophenotype (increased frequency of CD34, CD11b and CD25), lack of leukemic progenitor cell suppression due to TGFbeta1, increased bcl-2 expression, presence of inducible nitric oxide synthase, lower levels or mrp transcripts and increased expression of p53. Possible interpretations of these differences between mAML and dAML are presented. Implications for mAML directed therapy are discussed.
 ...
PMID:Is myelodysplastic related acute myelogenous leukemia a distinct entity from de novo acute myelogenous leukemia? Potential for targeted therapies. 1137 67

A precancerous change has been identified incidentally in resected specimens from patients who have undergone cholecystectomy. We focused on chronic cholecystitis, showing a thick and sclerotic wall caused by recurrent inflammation, e.g. contracted cholecystitis, and examined the malignant potential of these lesions. We studied 88 patients who had undergone cholecystectomy. Contracted cholecystitis was diagnosed, using our criteria, in 28 of these cases. Ordinary chronic cholecystitis was diagnosed in 50 cases and gallbladder carcinoma in ten cases. We examined the expression of p53, Ki-67, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) immunohistochemically. Severe dysplasia or carcinoma in situ in a very small portion of the specimen was identified with hematoxylin-eosin staining in four cases (14.3%) of contracted cholecystitis. These specimens revealed a positive expression of not only p53, but also Ki-67, iNOS, and COX-2. Statistical significance was shown among the three disease groups in terms of the incidence of p53 overexpression, respectively (P<0.05). The results of this study suggest that contracted cholecystitis could be an early change leading to carcinogenesis.
 ...
PMID:Significance of contracted cholecystitis lesions as high risk for gallbladder carcinogenesis. 1141 Mar 19

PARP-1-deficient mice display a severe defect in the base excision repair pathway leading to radiosensitivity and genomic instability. They are protected against necrosis induced by massive oxidative stress in various inflammatory processes. Mice lacking p53 are highly predisposed to malignancy resulting from defective cell cycle checkpoints, resistance to DNA damage-induced apoptosis as well as from upregulation of the iNOS gene resulting in chronic oxidative stress. Here, we report the generation of doubly null mutant mice. We found that tumour-free survival of parp-1(-/-)p53(-/-) mice increased by 50% compared with that of parp- 1(+/+)p53(-/-) mice. Tumour formation in nude mice injected with oncogenic parp-1(-/-)p53(-/-) fibroblasts was significantly delayed compared with parp-1(+/+)p53(-/-) cells. Upon gamma-irradiation, a partial restoration of S-phase radiosensitivity was found in parp-1(-/-)p53(-/-) primary fibroblasts compared with parp-1(+/+)p53(-/-) cells. In addition, iNOS expression and nitrite release were dramatically reduced in the parp-1(-/-)p53(-/-) mice compared with parp-1(+/+)p53(-/-) mice. The abrogation of the oxydated status of p53(-/-) cells, due to the absence of parp-1, may be the cause of the delay in the onset of tumorigenesis in parp-1(-/-)p53(-/-) mice.
 ...
PMID:Loss of poly(ADP-ribose) polymerase-1 causes increased tumour latency in p53-deficient mice. 1143 40

Recent studies have shown that somatostatin (SOM) inhibits interleukin 6 (IL-6) and interferon gamma (IFNgamma) production by lymphocytes and peritoneal macrophages, whereas substance P (SP) enhances these cytokines production. To define the mechanism of the cytokine production enhancements and inhibitions by SOM and SP, we examined the expression of apoptosis modulator, p53, Bcl-2, Bax, inducible nitric oxide synthase (iNOS), Fas, caspase-8 and nitric oxide (NO) in thioglycolate-elicited peritoneal macrophages. SOM caused up-regulation of p53, Bcl-2, Fas and caspase-8 activities, and down-regulation of iNOS expression and NO production. On the other hand, SP slightly induces p53 and highly induces Bcl-2, iNOS expression and NO production. These data suggest that apoptosis by SOM may occur by a Bax- and NO-independent p53 accumulation, and through Fas and caspase-8 activation pathways, and that the inducible expression of Bcl-2 and NO production by SP may contribute to prevent the signals of apoptosis by Bax, and via Fas and caspase-8 activation.
 ...
PMID:Regulation of apoptosis by somatostatin and substance P in peritoneal macrophages. 1149 78

The present study evaluated the significance of nitric oxide synthase (NOS), cyclooxygenase (COX) expression and p53 status in 55 patients with gastric adenocarcinoma and relationship of these molecular markers to tumor characteristics and metastatic potential. Immunohistochemical technique was used to identify the cellular location and distribution of the enzymes in the specific cells of gastric tumors. In gastric cancer tissue, the expression of inducible enzymes, iNOS and COX-2, increased significantly with increasing tumor stage (P=0.015, P=0.001, respectively), size (P=0.025, P=0.001, respectively) and the presence of metastases (P=0.002, P=0.015, respectively). The expression of constitutive enzymes, ecNOS and COX-1, followed the opposite pattern. COX-1 was significantly reduced in advanced gastric tumors (P=0.007) and tumors larger than 5 cm (P=0.007). Reduced expression of ecNOS was also observed in advanced gastric tumors; however, this did not reach statistical significance. 53% of gastric tumors showed accumulation of p53. This was significantly higher in advanced tumors (P=0.004), larger than 5 cm (P=0.015) with metastases (P<0.001). Gastric tumors positive for accumulation of p53 had significantly stronger expression of iNOS (P=0.018) and COX-2 (P=0.01) enzymes than tumors negative for this nucleophosphoprotein. We conclude, that tumor-associated nitric oxide production, as well as COX-2 overexpression, may promote gastric cancer progression by providing a selective growth advantage to tumor cells with non-functioning p53.
 ...
PMID:Expression of nitric oxide synthase, cyclooxygenase, and p53 in different stages of human gastric cancer. 1156 94

Significant activity of inducible nitric oxide synthase (iNOS) has been reported in tumour cells, including chronic lymphoid leukaemic cells. In this study, we analysed the expression of iNOS in 15 untreated patients with acute myeloid leukaemia (AML) and in 7 normal controls. Using flow cytometry and immunocytochemistry, we demonstrated that patients with AML had a high expression of iNOS when compared to controls. There was no correlation between the expression of iNOS and the expression of p53 and K, H, and N-ras mutation and expression, suggesting that the high expression of iNOS is independent of these proteins and could be the result of transcription factors expressed in AML.
 ...
PMID:Expression of inducible nitric oxide synthase is increased in acute myeloid leukaemia. 1171 73

In some neurological disorders, excessive nitric oxide (NO, nitrogen monoxide) produced by inducible and/or neuronal nitric oxide synthases (iNOS and nNOS) is able to combine with superoxide (O(minus sign)(2)) to form peroxynitrite (ONOO(minus sign)), which can then induce p53-dependent neural apoptosis. In the present study, experiments using p53 knock-out mice primary neural cells revealed that 3-morpholinosydnonimine hydrochloride (SIN-1), a peroxynitrite donor, triggered apoptosis, while p53-transcriptional activity was effectively suppressed in the absence of p53 molecules. This shows that SIN-1 was able to induce p53-dependent apoptosis in murine primary neural cells. The mechanism responsible for the SIN-1-induced accumulation of p53 molecules was then analyzed. Western blot analysis indicated that p53 accumulation caused by SIN-1 did not require p53 phosphorylation, whereas SIN-1 treatment triggered MAP kinase (MAPK) phosphorylation and pretreatment with the MAP kinase kinase (MEK) inhibitor U0126 inhibited p53 accumulation. Pretreatment of the neural cells with lovastatin, an inhibitor of p21(ras) signaling, greatly inhibited the accumulation of p53 induced by SIN-1. Northern blot and immunofluorescence analyses revealed that primary neural cells treated with SIN-1 had increased levels of p19 alternate reading frame (p19(ARF)) mRNA and protein, which is induced by MAPK and stabilizes the p53 protein. Our findings clearly show that the p21(ras)-MAPK-p19(ARF) pathway has an essential role in p53-dependent apoptosis triggered by peroxynitrite in neural cells.
 ...
PMID:3-Morpholinosydnonimine hydrochloride induces p53-dependent apoptosis in murine primary neural cells: a critical role for p21(ras)-MAPK-p19(ARF) pathway. 1189 Jul 36

The onset of vascular leakage and hemorrhagic diathesis is one of the life-threatening complications occurring in dengue patients, yet the pathogenic mechanisms are not well understood. In this study, we demonstrated that Abs against dengue virus nonstructural protein 1 (NS1) generated in mice cross-reacted with human endothelial cells and mouse vessel endothelium. After binding, mouse anti-NS1 Abs induced endothelial cell apoptosis in a caspase-dependent manner. Inducible NO synthase expression could be observed; it showed a time- and dose-dependent correlation with NO production. Endothelial cell apoptosis, characterized by exposure of phosphatidylserine on the cell surface and nuclear DNA fragmentation, was blocked by treatment with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester. Further studies demonstrated that the expression of Bcl-2 and Bcl-x(L) decreased in both mRNA and protein levels, whereas p53 and Bax increased after anti-NS1 treatment. Cytochrome c release was also observed. All of these effects could be inhibited by N(omega)-nitro-L-arginine methyl ester. Taken together, anti-NS1 Abs act as autoantibodies that cross-react with noninfected endothelial cells and trigger the intracellular signaling leading to the production of NO and to apoptosis. Endothelial cell damage may cause vascular leakage that contributes to the pathogenesis of dengue disease.
 ...
PMID:Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. 1209 67


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>