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)

Selenium is an essential trace element for human health, and it has received considerable attention for its possible role as an anticarcinogenic agent. The purpose of the present study was to determine whether changes in the amount and the chemical form of selenium would affect DNA methylation and whether this effect would be modified by arsenic. Caco-2 cells, a human colon cancer cell line, were exposed to 0, 1 or 2 micromol supplemental selenite/L and 0, 1 or 2 micromol supplemental arsenite/L for 7 d. DNA isolated from Caco-2 cells not treated with selenite was significantly (P: < 0. 0001) hypomethylated compared with that from cells treated with 1 or 2 micromol selenite/L. DNA isolated from Caco-2 cells not treated with arsenite was significantly (P: < 0.0001) hypomethylated compared with DNA isolated from cells treated with 1 or 2 micromol arsenite/L. In addition, methylation of the p53 promoter region of Caco-2 cells decreased when cells were cultured in the absence of selenite and in the absence of arsenite. Sixty weanling male Fischer 344 rats were fed a torula yeast-based diet supplemented with 0, 0.1 or 2 mg selenium/kg diet as either selenite or selenomethionine in the presence or absence of 5 mg arsenic/kg diet as arsenite for 6 wk. Similar to the results with Caco-2 cells, rats fed selenium-deficient diets had significantly (P: < 0.0001) hypomethylated liver and colon DNA compared with rats fed 0.1 or 2.0 microg selenium/g diets as either selenite or selenomethionine. Thus, alterations in DNA methylation may be a potential mechanism, whereby deficient dietary selenium increases liver and colon tumorigenesis.
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PMID:Dietary selenium and arsenic affect DNA methylation in vitro in Caco-2 cells and in vivo in rat liver and colon. 1138 81

Se-allylselenocysteine (ASC) is effective in inhibiting mammary epithelial cell growth in vitro and mammary carcinogenesis in vivo, but its mechanism is unknown. We recently reported that ASC reduces cell growth in a dose- and time-dependent manner, induces a loss of DNA integrity, and increases apoptosis. However, the level of ASC required for growth inhibition in vitro is 10- to 20-fold higher than that required in vivo. One possible explanation for this difference is that the cells used in in vitro studies have limited lyase activity required to release the allyl Se moiety from selenocysteine, whereas animals have abundant lyase activity in tissues. In the present study, we found that methionine gamma-lyase (MGL) added to culture medium containing ASC produced biological effects with lower levels of ASC, comparable to the selenium levels in plasma achieved during in vivo chemoprevention. The combination of 2.5 microM ASC and MGL inhibited the growth of TM12 cells and increased apoptosis without loss of DNA integrity. Treatment of TM12 cells with ASC and MGL resulted in an elevation of the protein levels of p53, Cip1/p21, and Kip1/p27, concomitant with a decrease in cyclins D1 and E and modest reductions in cyclin-dependent kinase inhibitors 4 and 2. Cells treated with ASC and MGL also showed decreased phosphorylation of retinoblastoma tumor-suppressor protein. Taken together, these results suggest that a physiologically relevant concentration of ASC with MGL exerts an inhibitory effect on cell growth and that this effect is likely to involve modulation of signaling pathways that suppress the phosphorylation of retinoblastoma tumor-suppressor protein.
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PMID:Activity of Se-allylselenocysteine in the presence of methionine gamma-lyase on cell growth, DNA integrity, apoptosis, and cell-cycle regulatory molecules. 1117 Feb 56

This experimental study was designed to evaluate the efficacy of associated naturally occuring antioxidants in the prevention of chemically induced breast cancer using DMBA in virgin female Wistar rats. Rats were randomly allocated to three groups: control group (CG; n = 20), induction group (IG; n = 100), and prevention group (PG; n = 70). A single dose (65 mg/kg) of DMBA was administered in the IG and PG animals at 50 days of age. PG animals also received a single dose of alpha-tocopherol (200 mg/rat) 1 hour after DMBA administration and an association of selenium (p-XSC, 40 ppm/day/rat) and ascorbic acid (540 mg/day/rat) in drinking water, daily, from carcinogenic induction until necropsy. Macroscopic study and pathology revealed a significantly lower development of neoplasms in the PG animals (p < 0.05); the number of rats with mammary tumors, breast cancer incidence, and the number of malignant breast tumors per rat as well as per tumor-bearing rat were significantly decreased in the PG animals. Other types of primary neoplasms existing in the IG animals totally disappeared in the PG animals. Immunostaining to hormone steroid receptors (ER and PR) and cathepsin D was similar in both groups. Overexpression of p53 and metallothioneine was significantly increased in the PG animals (p < 0.05) and immunostaining to bromodeoxiuridin and Ki-67 was also stronger in the remaining tumors in the PG animals. These data thus add to the accumulating evidence that those micronutrients in combination seem to be effective in reducing the incidence of malignant tumors. Nevertheless, remaining tumors seem to present more aggressive behavior and characteristics of drug resistance.
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PMID:Chemoprevention of DMBA-Induced Mammary Tumors in Rats by a Combined Regimen of Alpha-Tocopherol, Selenium, and Ascorbic Acid. 1134 29

Metal ions are essential components of biological systems; nevertheless, even essential elements may have toxic or carcinogenic properties. Thus, besides As(III) and Cd(II), also Ni(II) and Co(II) have been shown previously to disturb different types of DNA repair systems at low, non-cytotoxic concentrations. Since some metals exert high affinities for SH groups, we investigated whether zinc finger structures in DNA-binding motifs of DNA repair proteins are potential targets for toxic metal ions. The bacterial formamidopyrimidine-DNA glycosylase (Fpg protein) involved in base excision repair was inhibited by Cd(II), Cu(II) and Hg(II) with increasing efficiencies, whereas Co(II), As(III), Pb(II) and Ni(II) had no effect. Furthermore, Cd(II) still disturbed enzyme function when bound to metallothionein. Strong inhibition was also observed in the presence of phenylselenyl chloride, followed by selenocystine, while selenomethionine was not inhibitory. Regarding the mammalian XPA protein involved in the recognition of DNA lesions during nucleotide excision repair, its DNA-binding capacity was diminished by Cd(II), Cu(II), Ni(II) and Co(II), while Hg(II), Pb(II) and As(III) were ineffective. Finally, the H(2)O(2)-induced activation of the poly(ADP-ribose)polymerase (PARP) involved in DNA strand break detection and apoptosis was greatly reduced by Cd(II), Co(II), Ni(II) and As(III). Similarly, the disruption of correct p53 folding and DNA binding by Cd(II), Ni(II) and Co(II) has been shown by other authors. Therefore, zinc-dependent proteins involved in DNA repair and cell-cycle control may represent sensitive targets for some toxic metals such as Cd(II), Ni(II), Co(II) and Cu(II), as well as for some selenium compounds. Relevant mechanisms of inhibition appear to be the displacement of zinc by other transition metals as well as redox reactions leading to thiol/disulfide interchange.
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PMID:Interference by toxic metal ions with zinc-dependent proteins involved in maintaining genomic stability. 1206 81

The cancer chemopreventive properties of selenium compounds are well documented, yet little is known of the mechanism(s) by which these agents inhibit carcinogenesis. We show that selenium in the form of selenomethionine (SeMet) can activate the p53 tumor suppressor protein by a redox mechanism that requires the redox factor Ref1. Assays to measure direct reduction/oxidation of p53 showed a SeMet-dependent response that was blocked by a dominant-negative Ref1. By using a peptide containing only p53 cysteine residues 275 and 277, we demonstrate the importance of these residues in the SeMet-induced response. SeMet induced sequence-specific DNA binding and transactivation by p53. Finally, cellular responses to SeMet were determined in mouse embryo fibroblasts wild-type or null for p53 genes. The evidence suggests that the DNA repair branch of the p53 pathway was activated. The central relevance of DNA repair to cancer prevention is discussed.
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PMID:Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. 1239 10

Tumor suppressor p53 exhibits an enigmatic phenotype in cells exposed to electrophilic, cyclopentenone prostaglandins of the A and J series. Namely, cells harboring a wild-type p53 gene accumulate p53 protein that is conformationally and functionally impaired. This occurs via an unknown molecular mechanism. We report that electrophilic cyclopentenone prostaglandins covalently modify and inhibit thioredoxin reductase, a selenoprotein that governs p53 and other redox-sensitive transcription factors. This mechanism accounts fully for the unusual p53 phenotype in cells exposed to electrophilic prostaglandins. Based on this mechanism we derived, tested, and affirmed several predictions regarding the kinetics of p53 inactivation; the protective effects of selenium; the structure-activity relationships for inhibition of thioredoxin reductase and impairment of p53 by electrophilic lipids; the susceptibility of hypoxia-inducible factor to inactivation by electrophilic lipids; and the equivalence of chemical inactivation of p53 to deletion of a p53 allele. Chemical precepts dictate that other electrophilic agents should also inhibit thioredoxin reductase and impair its governance of redox-sensitive proteins. Our results provide a novel framework to understand how endogenous and exogenous electrophiles might participate in carcinogenesis; how selenoproteins and selenium might confer protection against cancer; how certain tumors might acquire their paradoxical p53 phenotype; and how chronic inflammation might heighten the risk for cancer.
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PMID:Electrophilic prostaglandins and lipid aldehydes repress redox-sensitive transcription factors p53 and hypoxia-inducible factor by impairing the selenoprotein thioredoxin reductase. 1242 31

Low levels of hepatic selenium (Se)-dependent glutathione peroxidase 1 (GPX1) activity have been shown to protect against oxidative liver injury in Se-deficient mice. The objective of the present study was to determine if the GPX1 protection was associated with phosphorylations of c-Jun N-terminal kinase (JNK) and p53 on Ser-15, two key signalling events in oxidative-stress-mediated cell death. Both Se-deficient GPX1 knockout (GPX1(-/-)) and wild-type (WT) mice ( n =64) were pretreated with an intraperitoneal injection of Se (as sodium selenite, 50 microg/kg body weight) 6 h before an intraperitoneal injection of paraquat (12.5 mg/kg). Liver aponecrosis, a mixed form of cell death sharing apoptosis and necrosis, was induced by paraquat in both groups of mice. However, its appearance was remarkably delayed and the severity was decreased by the repletion of hepatic GPX1 activity to <4% of the normal level by the Se injection in the WT mice, compared with that in the GPX1(-/-) mice. Consistently, the WT mice had lower levels of hepatic phospho-JNK, p53 and phospho-p53 (Ser-15) when compared with the GPX1(-/-) mice at 1-10 h after paraquat injection. Incubating liver homogenates with antibodies raised against JNK or phospho-JNK resulted in co-immunoprecipitation of phospho-p53 (Ser-15), and the amounts of the precipitated phospho-p53 were greater in the GPX1(-/-) mice when compared with that in the WT mice. The co-precipitated complex by the anti-phospho-JNK antibody was capable of phosphorylating intrinsic or extrinsic p53 on Ser-15. In conclusion, phospho-JNK may catalyse phosphorylation of p53 on Ser-15 in Se-deficient mouse liver under moderate oxidative stress, and attenuation of that cascade by low levels of GPX1 activity is associated with its protection against the pro-oxidant-induced liver aponecrosis.
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PMID:Low levels of glutathione peroxidase 1 activity in selenium-deficient mouse liver affect c-Jun N-terminal kinase activation and p53 phosphorylation on Ser-15 in pro-oxidant-induced aponecrosis. 1249

Multiple intestinal neoplasia (Min) mice are a good model for investigating the effects of dietary alterations in a genetic model for intestinal cancer. Previous studies have shown that selenium-enriched broccoli effectively reduces colon cancer susceptibility. Although colon cancer cells mainly metastasize to the liver, little is known about the effects of selenium-enriched broccoli on gene expression in mouse liver. To better understand the protective role for selenium-enriched broccoli in tumorigenesis, a gene profile of the mouse liver was analyzed. Mice were fed either 0.11 mg selenium/kg control diet or 2.1 mg selenium/kg selenobroccoli diets for 10 weeks. Use of mouse pathway finder-1 GEArrays revealed that selenium-enriched broccoli moderately increased ikBalphakappaB, hsp86, gadd45 gene transcripts. In addition, analysis of the binding of liver nuclear proteins to (32)P-labeled probes demonstrated that selenium-enriched broccoli enhanced the binding of transcription factor p53, NFkappaB, AP-1 to their cis-acting elements. Collectively, these results suggest for the first time that selenium-enriched broccoli activates certain pro-apoptotic genes linked to p53, NFkappaB and stress signal pathways in response to "danger signals" such as tumorigenesis.
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PMID:Effect of selenium-enriched broccoli diet on differential gene expression in min mouse liver(1,2). 1277 Jun 47

The generation of reactive oxygen species has been implicated in ultraviolet radiation (UVR)-induced skin damage. In mice, increasing dietary selenium intake protects skin from UVR-induced DNA damage and photocarcinogenesis. We sought to determine whether selenium supplementation could protect keratinocytes from apoptosis resulting from exposure to broadband (TL20W/12) UVR. Unirradiated cultures contained 6.5 +/- 1% apoptotic cells; the maximum percentage of apoptotic cells (34 +/- 5%) was seen 16 h after UVR of 600 J/m(2). Under these conditions cell death from necrosis was 15 +/- 2.5% of the total cells. A 24-h preincubation with sodium selenite (10 nm(-1) microm) or selenomethionine (50 nm(-1) microm) protected cultured human keratinocytes from UVR-induced apoptosis. In primary keratinocytes the greatest reduction in apoptosis was found with 100 nm of either selenium compound (71% reduction in the numbers of total apoptotic cells; P < 0.01). Supplementation with 100-200 nm selenite or selenomethionine prevented UVR-induced apoptosis, but did not decrease the levels of UVR-induced p53, as measured by Western blotting. Collectively, this data suggests that selenium prevents UVR-induced cell death by inhibiting p53-independent cell death pathways.
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PMID:Selenium protects primary human keratinocytes from apoptosis induced by exposure to ultraviolet radiation. 1278 Jul 18

Numerous recent investigations on the development and morphology of atherosclerotic lesions have shown programmed cell death or apoptosis to be an important factor in atherogenesis. Enzymes known as caspases are essential for completion of the apoptotic program. With regard to the origin of signals inducing apoptosis, there are two ways of initiating caspase activation: (a) cellular death receptor-mediated activation; and (b) activation mediated by mitochondrial permeability and expression of the p53 oncogene. Both of these pathways are involved in atherogenesis. Oxidative stress, angiotensin II and cholesterol overload are the primary factors that induce apoptosis in vascular cells. Considering apoptosis in endothelial cells, exposed phosphatidylserine on the cell membrane activates thrombin increasing the probability of arterial thromboses. Further progression of atherosclerosis is promoted by the formation of apoptotic bodies with oxidized phospholipids exposed on the membrane; these also activate adhesion of monocytes. Apoptosis of smooth muscle cells is usually observed in the fibrous portion of an atherosclerotic plaque in which the cells produce collagen important for plaque stability. As apoptosis occurs in smooth muscle cells, the fibrous cap grows thinner. This can result in both plaque rupture, formation of thrombi as well as calcification of the plaque from apoptotic smooth muscle cells remnants. Smooth muscle cells apoptosis is beneficial in that it offers protection to the walls of arteries against proliferative restenosis induced by invasive procedures. Apoptosis of macrophages contributes to the formation and progression of the lipidic core and promotes thrombosis of atherosclerosis in damaged arteries. By contrast, apoptosis of macrophages diminishes the production of matrix methaloproteinases that decompose collagen fibers. New facts concerning the effects of antioxidants (selenium, vitamin C and vitamin E), inhibitors of angiotensin converting enzyme, beta-blockers, calcium chanel blockers, and statins are also considered in this review.
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PMID:[Programmed cellular death and atherogenesis: from molecular mechanisms to clinical aspects]. 1282 74


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