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)

In this study, we investigated the relationship between genetic alterations such as chromosome 22 aneuploidy and p53 gene deletion, and the pathological types of meningioma of typical and aggressive forms. Thirty-four meningiomas (23 typical and 11 aggressive) were examined by application of fluorescence in situ hybridization (FISH) with chromosome 22 specific alpha satellite probe and a combination of p53 locus specific and chromosome 17 centromere specific alpha satellite probes, to evaluate the chromosome 22 aneuploidy and gain or loss of p53 gene along with chromosome 17. The results showed that, although chromosome 22 aneuploidy was seen in 7 out of 23 typical (30.4%) and 4 out of 11 aggressive meningiomas (36.3%), no p53 deletion was detected in typical meningiomas, and p53 deletion was detected in 3 out of 11 aggressive meningiomas (1 atypical and 2 malignant), which had recurrence. There were no simultaneous occurrences of p53 gene deletions between typical and aggressive meningiomas. The present findings indicate that the loss of chromosome 22 may be involved with tumorogenesis of typical and aggressive meningiomas, while p53 gene deletions may be involved with malignant progression and recurrence in the aggressive meningiomas.
Teratog Carcinog Mutagen 2002
PMID:Evaluation of relationship between chromosome 22 and p53 gene alterations and the subtype of meningiomas by the interphase-FISH technique. 1194 32

Merbarone is a catalytic inhibitor of topoisomerase II (topo II) that has been proposed to act primarily by blocking topo II-mediated DNA cleavage without stabilizing DNA-topo II-cleavable complexes. In this study merbarone was used as a model compound to investigate the genotoxic effects of catalytic inhibitors of topo II. The clastogenic properties of merbarone were evaluated using in vitro and in vivo micronucleus (MN) assays combined with CREST staining. For the in vitro MN assay, ICRF-187, a different type of catalytic inhibitor, and etoposide, a topo II poison, were used for comparison. Treatment of TK6 cells with all three of these drugs resulted in highly significant dose-related increases in kinetochore-lacking MN and, to a lesser extent, kinetochore-containing MN. In addition, a good correlation between p53 accumulation and MN formation was seen in the drug-treated cells. A mouse MN assay was performed to confirm that similar DNA-damaging effects would occur in vivo. Bone marrow smears from merbarone-treated B6C3F1 mice showed a dose-related increase in micronucleated polychromatic erythrocytes with a mean of 26 MN per 1000 cells being seen at the 60 mg/kg dose. Almost all MN lacked a kinetochore signal, indicating that merbarone was predominantly clastogenic under these conditions in vivo. The present study clearly shows that merbarone is genotoxic both in vitro and in vivo, and demonstrates the inaccuracy of earlier statements that merbarone and other catalytic inhibitors block the enzymatic activity of topo II without damaging DNA.
Environ Mol Mutagen 2002
PMID:Catalytic inhibitors of topoisomerase II are DNA-damaging agents: induction of chromosomal damage by merbarone and ICRF-187. 1211 87

A common polymorphism at codon 72 (Arg72Pro) of the p53 gene, a gene which codes for a tumor-suppressor protein with both antiproliferative and pro-apoptotic actions, has recently been reported to be a risk factor for coronary luminal narrowing after angioplasty. However, the association of the polymorphism with coronary artery disease (CAD) risk has not been studied. We evaluated the distribution of the Arg72Pro genotype in 250 patients, 180 with angiographically documented CAD and 70 with normal coronary angiography, by using polymerase chain reaction amplification of patient DNA followed by restriction enzyme digestion. We also examined the association between the Arg72Pro genotype and chromosome damage in 82 male patients (60 CAD and 22 no-CAD) by the micronucleus (MN) test in human lymphocytes, a sensitive assay for chromosome breakage and aneuploidy. The frequencies of Pro/Pro, Pro/Arg, and Arg/Arg genotypes in CAD patients were not significantly different from those who were CAD-free (chi(2) = 0.20, P = 0.90) and not significantly associated with the extent and severity of CAD. A significant increase in MN frequency was observed in relation to smoking status (8.4 +/- 0.6, 11.9 +/- 1 and 12.0 +/- 1.6, for non smokers, ex-smokers and smokers, respectively; P = 0.02). Moreover, diabetic patients showed higher levels of MN than normal patients (13.5 +/- 1.4 vs. 9.6 +/- 0.5, P = 0.0025). Also, MN frequency was significantly higher in CAD patients than in no-CAD patients (11.2 +/- 0.7 vs. 8.0 +/- 0.9, P = 0.02) and increased with the number of affected vessels (9.3 +/- 0.1, 12.2 +/- 1.5 and 12.5 +/- 1.3 for one-, two-, and three-vessel disease, respectively; P = 0.02). However, there were no associations between MN frequency and the Arg72Pro polymorphism. Although there appears to be an association between CAD and MN frequency, our results indicate that the Arg72Pro polymorphism does not have a significant impact on CAD or MN frequencies.
Environ Mol Mutagen 2002
PMID:P53 codon 72 polymorphism in coronary artery disease: no evidence for association with increased risk or micronucleus frequency. 1220 3

Environmental toxins induce multiple effects in vivo, involving various molecular pathways. The ultraviolet C (UVC, 254 nm) component of sunlight can cause strong cytotoxic and genotoxic effects. In this study, UVC-induced stress response factors were analyzed by cDNA microarray, using the Millennium(R) Nylon membrane chip system. HeLa cells were irradiated with 30 Joule/m(2)/sec UVC, incubated for 30 or 60 minutes and then subjected to the analysis. Multiple chips were used for each experimental condition so that the data could be analyzed statistically. Principal component analysis (PCA) was used to identify groups of genes whose expression changed in a similar manner with time post-UVC irradiation. Three major factors were identified, depending on the directionality of expression changes in each gene. The factor loadings in all three identified gene groups were high, indicating that genes within each group were highly correlated. Two factors exhibited significantly changed expression patterns after 30 minutes of incubation but in the opposite direction. This indicates that the "immediate early" UVC-induced stress response was elicited by two major pathways. Interestingly, expression of the genomic damage-inducible GADD genes, as well as p53, was initially decreased, unlike the "immediate early" genes Fos/Jun and Egr-1, which were strongly increased after 30 minutes of incubation. The results indicate that PCA used in the analysis of pre-hypothesized, functionally related genes can identify the potential subpathways in a group. This method provides a novel approach for identifying functionally-related genes in microarray studies.
Environ Mol Mutagen 2002
PMID:Two UVC-induced stress response pathways in HeLa cells identified by cDNA microarray. 1220 5

Conjugated linoleic acid (CLA) reduces mammary tumorigenesis in rodent models, induces apoptosis in rodent mammary tumor cell lines, and decreases expression of antiapoptotic bcl-2 in rat mammary tissue. This investigation focused on the cell mechanisms underlying the antitumor effects of CLA. Changes (mRNA, protein) in expression of major proapoptotic p53, p21WAF1/CIP1, bax, bcl-Xs genes, and the antiapoptotic bcl-2 gene were observed in malignant MCF-7 and MDA-MB-231 cells and in benign MCF-10a human mammary tumor cells in culture. CLA, but not linoleic acid (LA), inhibited proliferation in all cells; CLA mix was most effective. CLA increased DNA damage (apoptosis). CLA increased mRNA expression of p53 and p21WAF1/CIP1 (three- to fivefold and twofold, respectively) but either decreased bcl-2 by 20-30% or had no effect in MCF-7 and MCF-10a cells, respectively; protein expression reflected mRNA values. In MDA-MBA-231 (mutant p53) cells, mRNA for p53 was not changed, but p21WAF1/CIP1 and bcl-2 mRNA was increased. Protein expression largely reflected mRNA changes but, surprisingly, CLA completely suppressed mutant p53 protein in MDA-MB-231 cells. Apparent antiapoptotic effects of increased bcl-2 expression in MDA-MBA-231 cells were countered by increased proapoptotic p21WAF1/CIP1, Bax, and Bcl-Xs proteins. Findings indicate that CLA elicits mainly proapoptotic effects in human breast tumor cells through both p53-dependent and p53-independent pathways, according to cell type.
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PMID:Conjugated linoleic acids (CLAs) regulate the expression of key apoptotic genes in human breast cancer cells. 1220 43

The influence of the loss of p53 gene on heavy-ion-induced mutations was examined by constructing a new line of transgenic mice, p53 knockout (p53(-/-)) gpt delta. In this mouse model, deletions in lambda DNA integrated into the mouse genome are preferentially selected as Spi(-) phages, which can then be subjected to molecular analysis. Mice were exposed to 10 Gy of whole-body carbon-ion irradiation. The carbon ions were accelerated to 135 MeV/u by the RIKEN Ring Cyclotron. The p53 defect markedly enhanced the Spi(-) mutant frequency (MF) in the kidneys of mice exposed to C-ion irradiation: the Spi(-) MF increased 4.4- and 2.8-fold over the background level after irradiation in p53(-/-) and p53(+/+) mice, respectively. There was no significant difference in the background Spi(-) MF between p53(-/-) and p53(+/+) mice. Sequence analysis of the Spi(-) mutants indicated that the enhancement of kidney Spi(-) MF in p53(-/-) mice was primarily due to an increase in complex or rearranged-type deletions. In contrast to the kidney, the p53 defect had no effect on the Spi(-) MF in liver: Spi(-) MF increased 3.0- and 2.7-fold after the irradiation in p53(-/-) and p53(+/+) mice, respectively. Our results suggest that p53 suppresses deletion mutations induced by heavy-ion irradiation in an organ-specific manner.
Environ Mol Mutagen 2002
PMID:Heavy-ion-induced mutations in the gpt delta transgenic mouse: effect of p53 gene knockout. 1235 56

The human Reprimo gene is a recently identified cytoplasmic protein, which plays an important role in the regulation of p53-dependent G2 arrest of the cell cycle. Genetic variations in the Reprimo gene that may influence enzyme activity can be of both biological and epidemiological significance. The human expressed sequence tag (EST) database is a wealth of resources, which can be used to rapidly screen for potential polymorphisms in proteins of physiological interest. On the basis of the alignment of human EST sequences, we identified two candidate polymorphisms at nucleotides 824 and 839 in the 3'-untranslated region of the Reprimo gene. The presence of these polymorphisms was confirmed in a Caucasian population (n=82) by the use of the allele specific polymerase chain reaction (PCR). The rare allele frequency at position 824 (38.4%) is much higher than rare allele frequency at position 839 (3.7%). Our results suggest that the human EST data may serve as a valuable source for the rapid identification of genetic variation.
Teratog Carcinog Mutagen 2002
PMID:Identification of polymorphisms in the human Reprimo gene using public EST data. 1239 9

The DNA repair proteins XPD and XRCC1 are involved in the nucleotide and base excision repair of DNA lesions induced by many tobacco and environmental carcinogens. Common variant alleles at the XPD (312Asn, 751Gln) and XRCC1 (399Gln) loci have been identified and associated with increased risk for lung cancer. We therefore investigated a possible effect of these variant alleles on the frequency and spectrum of p53 mutations in the tumors of 97 Swedish lung cancer patients (56 never-smokers and 41 age-, gender-, and hospital-matched ever-smokers). The p53 gene was mutated in 4 never-smokers (7%) and 11 ever-smokers (27%). Smoking-related transversion-type mutations predominated over transitions among smokers (8:3), but not among never-smokers (1:3). None of the variant alleles altered the overall frequency of p53 mutation. Transversions, however, were marginally increased among patients with at least one XPD variant allele compared with patients who were wild-type homozygotes (73% vs. 25% for the Asp312Asn polymorphism, P = 0.095; 78% vs. 33% for Lys751Gln, P = 0.085). Five of six women or six of seven smokers who carried at least one XPD 751Gln allele had p53 transversion. The XRCC1 variant allele did not show any effect on the p53 mutation. We conclude that the XPD variant alleles may be associated with an increased frequency of smoking-related p53 mutations in lung tumors, presumably due to reduced DNA repair proficiency.
Environ Mol Mutagen 2003
PMID:Influence of common XPD and XRCC1 variant alleles on p53 mutations in lung tumors. 1255 90

It would be advantageous to measure mutation load in situ in order to determine the relationship between a high mutation load and increased risk for cancer or other diseases and to evaluate sources of possible mutagen exposure. Previously, in situ mutation detection assays have been plagued with multiple rounds of amplification and high rates of false-positives and false-negatives. The single cell immunohistochemical mutation load assay (SCIMLA) was developed to measure somatic mutation frequency, pattern, and spectrum in normal tissues with a single round of amplification. The P53 gene was utilized as a mutation reporter because of the unusual property that missense mutations often cause P53 protein to accumulate in the cell, allowing the mutant proteins to be detected by immunohistochemical staining. Alternative reporter genes with stabilized mutant proteins may be envisioned. Single cells that stain positively for P53 protein overabundance (red cells) were microdissected from ethanol-fixed and paraffin-embedded tissues. A novel stimulated-PCR (S-PCR) protocol permitted successful amplification of a 1.8-kb segment of the P53 gene (i.e., exons 5-9) in 87% of single mammary cells. Subsequent sequence analysis demonstrated that 35% of the amplified red-stained epithelial cells from normal breast tissue have missense mutations at evolutionarily conserved amino acids. Jackpot mutations, presumably due to clonal expansion, were common. False-positive missense mutations at conserved residues were observed in 3% of the clear cells (i.e., without red stain), presumably due to DNA polymerase error in early PCR cycles. The allele dropout rate was measured at 40% of the amplified cells. SCIMLA is applicable to a variety of tissues, utilizes a single amplification of an endogenous gene, displays mutant cells in situ, and may be adapted to other species.
Environ Mol Mutagen 2003
PMID:Single-cell immunohistochemical mutation load assay (SCIMLA) using human paraffin-embedded tissues. 1455 27

Nitric oxide (NO(.)), which is generated under chronic inflammatory conditions that predispose individuals to cancer, has paradoxical effects. NO(.) can activate p53, which can result in anti-carcinogenic effects, or it can be mutagenic and increase cancer risk. We explored the mechanisms by which NO(.) induced p53 activation in vitro and found that NO(.) induced p53 accumulation and phosphorylation, particularly at ser-15, via ATM and ATR kinases, which then led to cell cycle arrest at G(2)/M. We next examined proteins in these pathways in both inflamed and normal human colon tissue. Inducible nitric oxide synthase (iNOS) levels and p53-P-ser15 levels were positively correlated with the degree of inflammation and with each other. Additionally, the p53 targets, HDM-2 and p21 (WAF1), were present in ulcerative colitis (UC) colon, but undetectable in normal colon, consistent with activated p53. We also found higher p53 mutant frequencies of both G:C --> A:T transitions at the CpG site of codon 248 and C:G --> T:A transitions at codon 247 in lesional colon tissue from UC cases versus nonlesional tissue from these cases or colon tissue from normal adult controls. Consistent with nitrosative stress and the deamination of 5-methylcytosine, p53 mutations were also detected in sporadic colon cancer tissue and were associated with iNOS activity in these tissues. These studies identified a potential mechanistic link between NO(.) and p53 in UC and sporadic colon cancer.
Environ Mol Mutagen 2004
PMID:Nitric oxide and p53 in cancer-prone chronic inflammation and oxyradical overload disease. 1519 42


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