UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is now well established that oxidized LDL (OxLDL) is involved in the progression of the atheromatous plaque via several mechanisms, including its cytotoxicity toward the arterial wall. Our study demonstrates that a 4-h incubation of cultured human fibroblasts with 25-75 microg/ml OxLDL induced a dose-dependent increase in the intracellular levels of reactive oxygen species (ROS) and lipid peroxidation end products (TBARS). This effect was markedly prevented by the antioxidant vitamin E. The lipid extract of OxLDL partially reproduced the action of the LDL particle itself. Concomitantly, OxLDL enhanced the DNA binding activity of p53 measured by electrophoretic mobility shift assay, and the intracellular protein level of p53 determined by immunoblot analysis. Cycloheximide prevented the OxLDL-induced augmentation in both p53 binding activity and intracellular level. Again, the lipid extract of OxLDL reproduced the effect of OxLDL on p53 binding activity, whereas vitamin E prevented it. These results indicate that OxLDL initiates an intracellular oxidative stress by means of its lipid peroxidation products, leading to the activation of the tumour suppressor p53 by enhancement of p53 protein synthesis. This effect might be related to the cytotoxic effect of OxLDL since the activation of p53 is known to lead to cell cycle arrest, necrosis or apoptosis.
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PMID:Oxidized LDL induces an oxidative stress and activates the tumor suppressor p53 in MRC5 human fibroblasts. 1102 37

Alterations in DNA methylation have been associated with cancers at almost all tumor sites and represent one of the most consistent changes in neoplastic cells. The underlying etiological mechanisms for alteration of DNA methylation patterns are not understood, but experimental studies in animals suggest potential environmental and genetic influences. The purpose of this study was to investigate whether DNA hypomethylation in peripheral blood DNA (potentially representing status at the lung) was associated with increased risk for the development of lung cancer. We evaluated genome-wide and p53 gene-specific hypomethylation in 100 lung cancer cases and controls selected from a large clinical trial of male smokers, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Genome-wide methylation status was assessed using the in vitro methyl acceptance capacity assay and p53 gene-specific methylation status using the HpaII quantitative PCR assay. Hypomethylation was evaluated as a risk factor using multivariate conditional logistic regression analyses. Genome-wide methylation status was unrelated to lung cancer risk; the odds ratio was 1.25 and the 95% confidence interval was 0.48-3.21 for those in the highest versus lowest quartile of hypomethylation status. Hypomethylation of the p53 gene in exons 5-8, the hypermutable region, was associated with a 2-fold increased risk for lung cancer (odds ratio, 2.20; 95% confidence interval, 1.04-4.65), whereas there was no risk increase for hypomethylation at exons 2-4, a region of the gene not known for its mutability or functional significance in cancer. Our results indicate that hypomethylation status within exons 5-8 of p53 from peripheral lymphocyte DNA may be a relevant predictor of lung cancer among male smokers.
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PMID:Hypomethylation of p53 in peripheral blood DNA is associated with the development of lung cancer. 1120 92

Zinc has several crucial functions in brain development and maintenance: it binds to p53, preventing it from binding to supercoiled DNA and ensuring that p53 cause the expression of several paramount genes, such as the one that encodes for the type I receptors to pituitary adenine cylase-activator peptide (PACAP), which directs embryonic development of the brain cortex, adrenal glands, etc.; it is required for the production of CuZnSOD and Zn-thionein, which are essential to prevent oxidative damage; it is required for many proteins, some of them with Zn fingers, many of them essential enzymes for growth and homeostasis. For example, the synthesis of serotonin involves Zn enzymes and since serotonin is necessary for melatonin synthesis, a Zn deficiency may result in low levels of both hormones. Unfortunately, Zn levels tend to be low when there is excess Cu and Cd. Moreover, high estrogen levels tend to cause increased absorption of Cu and Cd, and smoking and eating food contaminated with Cd result in high levels of the latter. Furthermore, ethanol ingestion increases the elimination of Zn and Mg (which acts as a cofactor for CuZnSOD). Increased Cu levels may also be found in people with Wilson's disease, which is a rather rare disease. However, the heterozygote form (only one faulty copy of the chromosome) is not so rare. Therefore, the developing fetus of a pregnant women who is low in Zn and high in Cu may experience major difficulties in the early development of the brain, which may later manifest themselves as schizophrenia, autism or epilepsy. Similarly, a person who gradually accumulates Cu, will tend to experience a gradual depletion of Zn, with a corresponding increase in oxidative damage, eventually leading to Parkinson's disease. Also discussed are the crucial roles of histidine, histamine, vitamin D, essential fatty acids, vitamin E, peroxynitrate, etc. in the possible oxidative damage involved in these mental diseases.
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PMID:Micronutrient accumulation and depletion in schizophrenia, epilepsy, autism and Parkinson's disease? 1138 83

Cytosine arabinoside (AraC) is a nucleoside analog that produces significant neurotoxicity in cancer patients. The mechanism by which AraC causes neuronal death is a matter of some debate because the conventional understanding of AraC toxicity requires incorporation into newly synthesized DNA. Here we demonstrate that AraC-induced apoptosis of cultured cerebral cortical neurons is mediated by oxidative stress. AraC-induced cell death was reduced by treatment with several different free-radical scavengers (N-acetyl-L-cysteine, dipyridamole, uric acid, and vitamin E) and was increased following depletion of cellular glutathione stores. AraC induced the formation of reactive oxygen species in neurons as measured by an increase in the fluorescence of the dye 5-(6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate. AraC produced DNA single-strand breaks as measured by single-cell gel electrophoresis and the level of DNA strand breakage was reduced by treatment with the free radical scavengers. These data support a model in which AraC induces neuronal apoptosis by provoking the generation of reactive oxygen species, causing oxidative DNA damage and initiating the p53-dependent apoptotic program. These observations suggest the use of antioxidant therapies to reduce neurotoxicity in AraC chemotherapeutic regimens.
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PMID:Oxidative stress mediates neuronal DNA damage and apoptosis in response to cytosine arabinoside. 1146 62

The oral use of chewing tobacco has greatly increased in recent years, and this usage is associated with cancers of the mouth, lip, nasal cavities, esophagus and gut. Oral cancer accounts for 3% of all cancers in U.S.A. and is the seventh most common cancer. Previous studies in our laboratory have demonstrated the protective abilities of a novel IH636 grape seed proanthocyanidin extract (GSPE) against reactive oxygen species both in vitro and in vivo models, and provided significantly better protection as compared to vitamins C, E and beta-carotene. In the recent past, we have demonstrated smokeless tobacco (STE)-induced oxidative stress, apoptotic cell death in a primary culture of normal human oral keratinocytes (NHOK), and have compared the protective abilities of vitamins C and E, singly and in combination, and GSPE in this pathobiology [Free Rad. Biol. Med., 26, 992-1000 (1999)]. In the present study, we have assessed the protective role of vitamins C and E, and GSPE against STE-induced modulation of intracellular oxidized states in NHOK cells as demonstrated by laser scanning confocal microscopy. Approximately 11%, 26%, 28% and 50% protection were observed following incubation with vitamin C, vitamin E, a combination of vitamins C plus E, and GSPE, respectively. DNA fragmentation was assessed as an index of oxidative DNA damage and similar results were observed. Furthermore, the cellular viability and functional roles of Bcl-2, p53 and c-myc genes were assessed in STE-induced oxidative stress in NHOK cells. NHOK cells were treated with STE (0-200 micrograms/ml) for 24 h and changes in the expression of Bcl-2, p53 and c-myc genes were measured by reverse transcriptase-polymerase chain reaction (RT-PCR), and the protective effect of GSPE was assessed. Approximately a 2.0-fold increase in p53 gene expression was observed following incubation of the oral keratinocytes with 100 micrograms/ml of STE, beyond which the expression of p53 decreased, confirming increased apoptotic cell death with a higher concentration of STE as reported earlier. GSPE significantly modulated STE-induced changes in p53. The expression of antiapoptotic Bcl-2 gene decreased with STE treatment and the expression of Bcl-2 gene increased significantly following preincubation with GSPE. No significant change in the expression of transcription factor c-myc gene responsible for cell cycle growth was observed following incubation with STE and/or GSPE. Thus, c-myc may not be involved in STE-induced cytotoxicity towards NHOK cells. These results suggest that antioxidant protection of STE-induced cellular injury is associated with alterations in Bcl-2 and p53 expression.
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PMID:Protective effects of antioxidants against smokeless tobacco-induced oxidative stress and modulation of Bcl-2 and p53 genes in human oral keratinocytes. 1169 99

Immunohistochemical techniques were used to study the expression of "wild type" p53 and "mutant" p53 in experimental cancer inhibition by vitamin E. The cancer model used was the squamous cell carcinoma of hamster buccal pouch induced by the carcinogen 7,12 dimethylbenz(a)anthracene (DMBA). Cancer development was studied sequentially for 8-14 weeks and specimens prepared for histological and immunohistochemical interpretation. Primary antibodies used were monoclonal antibodies for "wild type" and "mutant" p53. Specificity of antibodies was confirmed by flow cytometry. Peroxidase-antiperoxidase staining was used on the tissue specimens. In those animals receiving vitamin E the buccal pouch tumour development was significantly inhibited and there was a notable expression of "wild type" p53. There was also a relative absence of "mutant" p53 in the buccal pouch lesions of animals receiving vitamin E. These observations suggest that vitamin E may inhibit cancer formation by stimulating the expression of a cancer suppressor gene.
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PMID:p53 in the anticancer mechanism of vitamin E. 1170 28

The undesired side-effects of haloperidol treatment include a number of extrapyramidal side-effects which have been proposed to result from drug-induced damage to the basal ganglia. The drug also causes irregular movements and locomotor patterns in experimental animals. Here we show that haloperidol treatment in rats is associated with increases in the expression of p53 and the ratio of pro-apoptotic (Bax) to anti-apoptotic (Bcl-2/Bcl-x(L)) proteins in the hippocampus and caudate putamen (CPu). In addition, haloperidol induces the DNA binding activity of the redox-sensitive nuclear factor-kappa B (NF-kappaB) and concomitantly upregulates the levels of the phosphorylated form of IkappaBalpha protein in vivo. Similar responses are observed when a mouse hippocampal cell line (HT-22) is treated with haloperidol and/or vitamin E. Interestingly, all of these biochemical effects of haloperidol are significantly attenuated when animals or cultured cells are pretreated with alpha-tocopherol (vitamin E). Consistent with this, vitamin E is demonstrated to substantially reduce the haloperidol-induced impairment of locomotor activity in rats. Collectively, the data indicate the usefulness of vitamin E as an adjunct to haloperidol treatment and provide initial clues about the underlying molecular mechanisms involved in these effects.
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PMID:Mechanisms underlying the protective potential of alpha-tocopherol (vitamin E) against haloperidol-associated neurotoxicity. 1185 Jan 54

Alpha-tocopheryl succinate (alpha-TOS), a redox-inactive analogue of vitamin E, is a strong inducer of apoptosis, whereas alpha-tocopherol (alpha-TOH) lacks apoptogenic activity (J. Neuzil et al., FASEB J., 15: 403-415, 2001). Here we investigated the possible antineoplastic activities of alpha-TOH and alpha-TOS and further explored the potential of alpha-TOS as an antitumor agent. Using nude mice with colon cancer xenografts, we found that alpha-TOH exerted modest antitumor activity and acted by inhibiting tumor cell proliferation. In contrast, alpha-TOS showed a more profound antitumor effect, at both the level of inhibition of proliferation and induction of tumor cell apoptosis. alpha-TOS was nontoxic to normal cells and tissues, triggered apoptosis in p53(-/-) and p21(Waf1/Cip1(-/-)) cancer cells, and exerted a cooperative proapoptotic activity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) due to differences in proapoptotic signaling. Finally, alpha-TOS cooperated with tumor necrosis factor-related apoptosis-inducing ligand in suppression of tumor growth in vivo. Vitamin E succinate is thus a potent and highly specific anticancer agent and/or adjuvant of considerable therapeutic potential.
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PMID:Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo. 1189 20

Oxidized low density lipoprotein (OxLDL) is known to be cytotoxic towards different cell types of the arterial wall, leading to progression of an atherosclerotic plaque. We previously reported that OxLDL activates the tumor suppressor p53 in human fibroblasts [Biochem. Biophys. Res. Commun. 276 (2000) 718]. In the present work, we demonstrate that OxLDL increased intracellular levels of the kinase inhibitor p21(waf1) (p21) and of the tumor suppressor Rb. Concomitantly, level of the hypophosphorylated active form of Rb (HypoP-Rb) was also enhanced. Cycloheximide prevented the OxLDL-induced increase in p21, Rb, and HypoP-Rb, whereas okadaic acid had no effect. This increase was also prevented by the antioxidant vitamin E. In addition, the lipid extract of OxLDL, which includes the lipid peroxidation products, reproduced the action of the OxLDL particle itself. OxLDL and its lipid extract induced an oxidative stress, as assessed by the intracellular levels of reactive oxygen species and lipid peroxidation products. Finally, OxLDL induced a dose-dependent inhibition of DNA synthesis as assessed by thymidine incorporation. These results demonstrate that OxLDL or its lipid peroxidation products, by generation of an oxidative stress, enhances the expression of p21 and Rb genes, leading to an accumulation of the Hypo-P active form of the tumor suppressor Rb. This phenomenon is in accordance with the fact that p21 is a mediator of p53-dependent cell-cycle arrest in G1 and is most probably involved in the cytotoxicity of OxLDL.
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PMID:Oxidized low density lipoprotein induces the cyclin-dependent kinase inhibitor p21(waf1) and the tumor suppressor Rb. 1205 58

Pre-term neonates and neonates in general exhibit physiological vitamin E deficiency and are at increased risk for the development of acute lung diseases. Apoptosis is a major cause of acute lung damage in alveolar type II cells. In this paper, we evaluated the hypothesis that vitamin E deficiency predisposes alveolar type II cells to apoptosis. Therefore, we measured markers of apoptosis in alveolar type II cells isolated from control rats, vitamin E deficient rats and deficient rats that were re-fed a vitamin E-enriched diet. Bax and cytosolic cytochrome c increased, and the mitochondrial transmembrane potential and Hsp25 expression was reduced in vitamin E deficiency. Furthermore, increased DNA-fragmentation and numbers of early and late apoptotic cells were seen, but caspases 3 and 8 activities and expression of Fas, Bcl-2, Bcl-x and p53 remained unchanged. Vitamin E depletion did not change the GSH/GSSG ratio and the activities of antioxidant enzymes. Thus, vitamin E deficiency may induce a reversible pro-apoptotic response in lung cells and sensitise them for additional insult. In agreement with this hypothesis, we demonstrate that in vivo hyperoxia alone does not induce apoptosis in type II cells of control rats but reversibly increases DNA-fragmentation and numbers of early apoptotic type II cells in vitamin E-depleted cells.
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PMID:Vitamin E deficiency sensitizes alveolar type II cells for apoptosis. 1206 53

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