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)

Embryonic fibroblasts derived from p53-deficient transgenic mice showed distinct phenotypic and biological changes in vitro. In this study, we investigated the possible impact of p53 on the synthesis of other cellular proteins by comparing the protein profiles of p53 null (-/-), hemizygous (+/-) and p53 positive homozygous (+/+) cells using high resolution two dimensional gel electrophoresis. A total of more than 850 proteins were detected in each cell line labeled with 35S-methionine by using computerized image analysis, and a number of proteins were detected with qualitative or quantitative changes in p53-/- cells and to a lesser extent in p53+/- cells. Specifically, seven proteins became undetectable, and no new proteins were detected in p53-/- cells. Neither newly expressed nor absent proteins were detected in p53+/- cell line. Quantitatively, a total of 97 and 59 proteins were detected with significant quantitative changes (3 fold or greater) in p53-/- and p53+/- cells, respectively. Generally, most protein changes fell into one of the following four patterns: 1) progressively decreased synthesis in cells from p53+/+ to p53+/- to p53-/- cells; 2) progressively increased synthesis in cells from p53+/+ to p53+/- to p53-/- cells; 3) decreased synthesis only in p53-/- cells; and 4) increased synthesis only in p53-/- cells. A 70 kD heat shock protein (Hsp 70) was identified and showed a greater than 1,000-fold increase in p53-/- cells compared to that in p53+/+ cells. Transferrin, tropomyosin, and proliferating cell nuclear antigen (PCNA) have also been identified and measured in this study. Synthesis of transferrin and tropomyosin was significantly increased or decreased, respectively in p53-/- cells, whereas expression of PCNA showed no significant change in p53-/- cells despite their much higher (3-4 times) proliferation rate than the other two cell lines (p53+/+ and p53+/- cells). We conclude that disruption of a single important gene, p53, results in a cascade of protein changes which are related to the loss of p53 mediated negative growth effects on cell cycle control.
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PMID:Altered protein synthesis in p53 null and hemizygous transgenic mouse embryonic fibroblasts. 853 50

Baculovirus expression of human p53 protein, a nuclear cell cycle regulator, was examined in Sf9 cells and compared to native p53 synthesized in primary human cells. Maximum expression of the recombinant p53 protein occurred 48 h postinfection. De novo synthesis of the protein was evident for only 2 days postinfection; however, in pulse-chase studies, 30% of the synthesized protein remained stable up to 5 days. Seventy-seven percent of immunoprecipitated, [35S]-methionine-labeled, recombinant p53 protein resided in the cytoplasm of Sf9 cells, while 15% localized to the nucleus and 8% was released extracellularly. Separation of modified p53 protein, by charge and molecular weight, was accomplished by two-dimensional PAGE, and the electrophoretic pattern of the recombinant protein was identical to the wild-type protein from primary human mammary epithelial cells, indicating that the posttranslational modifications of the recombinant protein in this system are similar to those in primary human cells. Eleven isoforms focused between pI 5.75 and pI 6.5. The recombinant p53 isoforms were phosphorylated by 32P-labeling. Phosphatase digestion of immunoprecipitated p53 effectively removed phosphorous groups from the recombinant protein, reducing the number of isoforms from 11 to 2, demonstrating that phosphorylation is the major posttranslational event in the recombinant protein.
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PMID:Human p53 expressed in baculovirus-infected Sf9 cells displays a two-dimensional isoform pattern identical to wild-type p53 from human cells. 865 6

Mutations in the p53 tumor suppressor gene and the K-ras proto-oncogene are common genetic defects in lung cancer. Analysis of the patterns of damage in these genes may provide important insights into the mechanisms by which environmental mutagens initiate cancer. Previously, our laboratory found that a rare p53 codon 249 mutation (AGG(ARG) to ATG(MET) transversion) was present in 31% of a series of 52 large and squamous cell lung cancers from uranium miners, suggesting that this mutation might be a marker for radon exposure. In the current study, we analyzed 23 lung adenocarcinomas from the same cohort of highly exposed uranium miners. These tumors failed to show the codon 249 transversion, but 9 (39%) of 23 contained 1 or more mutations within hotspots in the K-ras gene. The results suggest that there is a histological tissue-type specificity for the codon 249 mutation; although this mutation was common in squamous and large cell tumors from very highly exposed uranium miners, it is rare in adenocarcinomas from the same cohort of miners.
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PMID:p53 and K-ras in radon-associated lung adenocarcinoma. 867 98

Although numerous studies have demonstrated increased expression of p53 protein in the Reed-Sternberg cells of Hodgkin's disease, little data exist as to whether mutations of the p53 gene is a common occurrence in this neoplasm. Using a microdissection technique coupled with PCR, single-strand conformation analysis, and DNA sequencing, we studied 23 cases of Hodgkin's disease for mutations within exons 5 to 8 of the p53 gene. We found seven mutations within six cases; six were missense mutations. An identical missense mutation was found in three cases (codon 243, methionine to isoleucine), and another identical missense mutation was found in an additional two cases (codon 204, glutamic acid to lysine). Verification of the mutations was accomplished either by direct Southern blotting of PCR-amplified p53 exon products from re-extracted DNA or by hybridization of cloned PCR-amplified p53 exon products from re-extracted DNA with a mutant-specific oligonucleotide. There was no good correlation between the presence of p53 mutations and the level of p53 protein expression, which was found to be overexpressed in all cases, the level of MDM2 protein expression, or the proliferation rate as determined by K-67 antibody. None of the cases with p53 mutation had evidence of Epstein-Barr virus within the Reed-Sternberg cells, as compared with 7 of 17 of the other cases (p < 0.06). These results suggest that p53 mutation may represent an important mechanism in the pathogenesis of Hodgkin's disease, and this mechanism may be independent of Epstein-Barr virus.
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PMID:p53 mutations in Hodgkin's disease. 887 83

In squamous cell carcinomas (SCCs), the tumor suppressor protein p53 is frequently overexpressed. The overexpression of p53 is often due to a mutation in the p53 gene; however, increased levels of p53 protein can be observed in the tumors without p53 gene mutations. In normal human keratinocytes, p53 is a multiconformational protein. The different conformations of p53 can be identified by their reactivity with epitope-specific, anti-p53 monoclonal antibodies. This study provides evidence that the different p53 conformations seen in human keratinocytes bind to distinct cellular proteins. Proteins that bind p53 in normal human keratinocytes were compared with p53-binding proteins from cells derived from SCC tumors by immunoprecipitation of [35S]methionine-labeled and 32P(i)-labeled cell lysates using a panel of anti-p53 monoclonal antibodies. In one tumor, the SCC cells contained a protein of Mr 30,000 bound to p53 that was not seen in normal human keratinocytes. Cells derived from a separate SCC did not have the Mr 30,000 protein but did contain two proteins of Mr 15,000 and Mr 16,000, which were not seen in normal human keratinocytes. The immunofluorescent staining pattern of cultured normal human keratinocytes, cells derived from two SCCs, as well as the original tumors from which the cells were derived, was also examined. The immunofluorescent staining of the cells derived from the tumors and the tumors themselves was different from that seen in normal cultured keratinocytes and normal epidermis. These studies suggest that there are alterations in the proteins that bind to p53 in SCCs.
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PMID:p53-binding proteins in squamous cell carcinoma and normal human keratinocytes. 901 65

We identified four families in which we suspected the presence of genetic factors predisposing them to cancer. We examined one family with features suggesting Li-Fraumeni syndrome for the presence of a germline p53 mutation in 13 of its members. To detect germline p53 mutations we performed polymerase chain reaction/nonradioisotopic single-strand conformation polymorphism and DNA sequencing analysis on exons 4-9 of the p53 gene. Mutated polymerase chain reaction-restriction fragment length polymorphism analysis was also performed on exon 5 to confirm the mutation identified by the sequencing analysis. A novel germline p53 mutation was identified at codon 133 (ATG-->AGG) in exon 5, resulting in the substitution of arginine for methionine, in all four cancer-affected individuals and in three apparently healthy individuals. We also analyzed tumor specimens for additional p53 mutations in the wild-type alleles using the same methods. However, heterozygosity was retained, and no other additional mutations in the wild-type allele were identified in any of the tumor tissues. It is possible that additional mutations in the wild-type allele are not always necessary for the loss of tumor suppressor functions. This study presents serious clinical and ethical problems about the predictive value of identifying germline p53 mutations in presymptomatic carriers. However, accurate predictive testing will be very useful in identifying unaffected individuals who are at increased risk of developing cancer and in detecting cancer at an early stage.
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PMID:Germline p53 mutation at codon 133 in a cancer-prone family. 902 Mar 84

The p53 gene was examined for point mutations in archived, alpha-radiation-associated lung and liver cancers. Lung tumors of 50 uranium miners in Germany were screened by restriction fragment length analysis for the putative hotspot mutation at codon 249 (Arg-->Met) previously detected in a significant fraction of miners from the Colorado Plateau, USA. This mutation has been proposed as a marker of radon exposure. None of the tumors we examined harbored the hotspot mutation. Five of the 50 tumors, however, did indeed harbor exon 7 mutations, as determined by subsequent mutation analysis of exon 7. These mutations were dispersed among various codons and may be attributable to heavy tobacco smoking in this cohort. In support of this interpretation, we found no mutations in exons 5-8 of the p53 gene in 13 iatrogenic liver cancers induced by injection of Thorotrast, an alpha-emitting radiocontrast agent. We propose that if the p53 tumor suppressor gene is a target for the carcinogenic action of alpha-particle radiation, loss of suppressor function may occur preferentially by mechanisms such as intrachromosomal deletions, rather than by base substitution mutations.
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PMID:p53 gene mutation analysis in tumors of patients exposed to alpha-particles. 906 50

Alteration of the p53 gene is thought to be important in the early stages of human esophageal cancers, but how this confers a selective advantage to esophageal cancer cells is unknown. In this report, we analyzed 9 cell lines derived from human esophageal cancers (TE-1, TE-3, TE-6, TE-7, TE-9, TE-10, TE-11, TE-13 and TE-15) for mutations in the p53 sequence, p53 protein expression and p53 protein DNA-binding activity. The cell lines could be grouped in 3 categories, including (1) cell lines with mis-sense mutations in the coding sequence and accumulation of mutant proteins (TE-1, TE-6, TE-10 and TE-11); (2) cell lines expressing truncated forms of p53 as a result of frameshift (TE-9) or splice-site (TE-15) mutations; and (3) cell lines with wild-type p53 sequences but with impaired expression of p53 mRNA and protein, suggesting that p53 is inactivated by transcriptional repression (TE-3, TE-7 and TE-13). With the exception of TE-1, none of the cell lines exhibited p53-DNA-binding activity. In TE-1, a mutation at codon 272 (methionine to valine) generated a protein that retains basal DNA-binding activity, but that was not activated in response to DNA damage, suggesting that this mutation prevented p53 induction by genotoxic stress. Thus, p53 activity was impaired in all esophageal cell lines, including those containing wild-type p53 sequences.
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PMID:Inactivation of the p53 protein in cell lines derived from human esophageal cancers. 909 69

Multiple doses of retinoic acid (RA) were administered intraperitoneally to three groups of male Fischer 344 rats over a 36 h period. The p53 isoforms from bone marrow nuclei in these three groups of rats were analyzed over time by two-dimensional polyacrylamide gel electrophoresis (PAGE) and fluorography for the incorporation of [35S]methionine (p53-synthesis) and [32P]phosphate (p53-phosphorylation). Two groups of rats, young (3.5 months) ad libitum (Y/AL) and old (28 months) ad libitum (O/AL), had free access to Purina rat chow; a third group of old (28 months) diet-restricted rats (O/DR) were maintained on a restricted caloric intake (60% of the AL diet) from 3 months of age. After 36 h of RA dosing, the PAGE patterns of p53 synthesis and phosphorylation in Y/AL and O/DR rats were very similar. In both groups, an increase in complexity was observed with labeling of additional isotypes possessing more acidic isoelectric values. In contrast, the O/AL animals showed a pattern of p53 isoform synthesis and phosphorylation that was considerably less complex and lacked the pronounced shift to more acidic forms following RA dosing. The p53 isoforms of O/AL rats as recognized by wild type (wt) Pab 246 antibody, were also much less dramatic in their increase to more acidic forms. Two-dimensional phospho-tryptic maps of Y/AL and O/DR rats were also very similar, both exhibiting two additional minor 32P-labeled fragments after RA dosing. The maps of O/AL rats did not show the two additional fragments following RA administration. After RA dosing, cyclin protein inhibitors (p16, p21, p27) revealed robust labeling with their respective antibodies in Y/AL and O/DR rats as analyzed by Western blotting. The O/AL animals showed marginally detectable antibody recognition of the cyclin inhibitors after RA dosing. Taken together, these data suggest that the biosynthesis and phosphorylation of p53 isoforms and the expression of cyclin dependent kinase inhibitor proteins is not significantly different between Y/AL and O/DR rats. Further, these results confirm and extend our previous observations that chronic diet-restriction attenuates the age related decline in the metabolic activity of nuclear protein products.
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PMID:P53 synthesis and phosphorylation in the aging diet-restricted rat following retinoic acid administration. 922 23

The CDKN2A gene encodes p16 (CDKN2A), a cell-cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1alpha and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis-sense mutation resulting in a methionine to isoleucine change at codon 53 (M531) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall-bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M531 change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi-site cancer families without melanoma are very unlikely to contain CDKN2A mutations.
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PMID:CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein. 938 68


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