Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Epigallocatechin gallate (EGCG) is a major water-soluble component of green tea. The antimutagenic activity of EGCG against benzo[a]pyrene (B[a]P)-induced mutations was assessed by using transgenic mice carrying the rpsL gene as a monitor of mutations. Seven-week-old male mice were given drinking water containing EGCG for 3 weeks. On day 7, mice were treated with a single i.p. injection of B[a]P (500 mg/kg body wt). Two weeks after the injection, the mutations in the rpsL gene were analyzed. B[a]P treatment resulted in an approximately 4-fold increase of mutation frequency at the rpsL gene in the lung. An approximately 60% reduction in the B[a]P-induced mutations in the lung was observed when mice were given EGCG at concentrations >0.005%. B[a]P-induced mutations mainly occurred at G:C basepairs in the several specific nucleotide sequences of the rpsL gene. These were AGG, CGG, CGT, TGG, TGC and GGT: all of them contained a guanine residue. Mutations seen similarly in the human Ki-ras codon 12 or p53 codons 157, 248, and 273 of lung tumor were also found in the rpsL gene, and the mutations were suppressed by the EGCG treatment. In conclusion, the antimutagenic effects of EGCG for B[a]P-induced mutagenesis in vivo suggest that drinking green tea may reduce the tumor-initiating potency of B[a]P in the lung.
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PMID:Inhibition of benzo[a]pyrene-induced mutagenesis by (-)-epigallocatechin gallate in the lung of rpsL transgenic mice. 1019 May 56

Both K-ras and p53 gene mutations are found commonly in pancreatic tumors. Analysis of the mutational patterns may provide insight into disease etiology. To further describe the mutational patterns of pancreatic cancer and to assess the evidence to date, we performed a pooled analysis of the published data on genetic mutations associated with pancreatic ductal adenocarcinoma. We included data from studies that evaluated point mutations in the two genes most studied in pancreatic cancer, K-ras and p53. A majority of the 204 tumors had mutations in at least one gene, with 29% having both K-ras and p53 mutations, 39% with K-ras mutation alone, and 16% having p53 mutation alone. Sixteen percent of tumors lacked mutation in either gene. K-ras mutations were present in high frequencies in all tumor grades (>69%). A statistically significant trend was observed for p53 mutation with higher tumor grade (P = 0.04). For K-ras, G2 and G3 grades, combined, had notably higher prevalences of mutation than G1 (P = 0.004). CGT mutations in K-ras codon 12 were marginally associated with lower tumor grade (P for trend = 0.09), and these tumors were somewhat less likely to have a p53 mutation than tumors with other K-ras mutations (P = 0.06). In the 59 K-ras+/p53+ tumors, 64% had the same type of mutation (transition or transversion) in both genes, suggesting a common mechanism. The mutational pattern of p53 in pancreatic cancer is similar to bladder cancer, another smoking-related cancer, but not to lung cancer. Analyses of molecular data, such as that performed here, present new avenues for epidemiologists in the study of the etiology of specific cancers.
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PMID:Patterns of genetic alterations in pancreatic cancer: a pooled analysis. 1021 65

Low-grade diffuse astrocytomas have an intrinsic tendency for malignant progression but the factors determining the kinetics of this process are still poorly understood. We report here the case of a male patient who developed a fibrillary astrocytoma at the age of 33 years and who underwent six surgical interventions over a period of 17 years without radiotherapy or chemotherapy. The first three biopsies spanned a period of 11 years and led to the diagnosis of low-grade, diffuse astrocytoma (WHO grade II), with a growth fraction (MIB-1 labeling index) of 2.3-3.7%. The fourth to sixth biopsies showed histological features of anaplastic astrocytoma (WHO grade III), with growth fractions between 5.0 and 10.5%. The fraction of gemistocytic neoplastic astrocytes also increased, from 0.3% in the first biopsy to 17.5% in the last biopsy and preceded the increase in proliferative activity and transition to anaplastic astrocytoma. The fraction of tumor cells immunoreactive to BCL-2 increased from 0.3% to 8.2%. A p53 mutation in codon 273 (CGT-->TGT, Arg-->Cys) was identified in the first biopsy and persisted throughout the course of the disease. However, the fraction of cells with p53 protein accumulation increased significantly during progression, from 3.2% in the first biopsy to 13.7% in the last. The absence of additional genetic alterations (PTEN mutations, loss of chromosome 10 and 19q) may be responsible for the slow progression and lack of glioblastoma features even after a 17-year disease duration.
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PMID:A case history of glioma progression. 1033 92

Adenocarcinoma of the pancreas generally remains an incurable disease by available treatment modalities, demanding the development of a suitable cell-culture/animal model and the discovery and evaluation of novel therapeutic agents. We report the clonal preservation of a human pancreatic cell line (KCI-MOH1) established from a 74-year-old African-American man diagnosed with pancreatic cancer. Initially the human primary tumor was grown as a xenograft in SCID mice and, subsequently, a cell line was established from tumors grown as a xenograft as reported in our earlier publication. The molecular characterization of the primary tumor, the tumors grown as xenograft, and the cell line all revealed similar genotypic properties. By using an automated DNA sequencer, a K-ras mutation (codon 12, GGT to CGT, Gly to Arg) was detected in the pancreatic tumor tissue taken from the patient, whereas no p53 mutation was detected. The same K-ras mutation and unaltered p53 was also found in the xenograft tumor and in the KCI-MOH1 cell line. Chromosome analysis of the cultured cells revealed: 42,XY,add(3)(p11.2),der(7)t(7;12) (p22;q12),-10,-12,add (14)(p11),-18,add (20)(q13),-22/84, idemx2, which is the same chromosome complement found in xenograft tumors. The KCI-MOH1 cell line grows well in tissue culture and forms tumors in the SCID mice when implanted subcutaneously, as well as in orthotopic sites. The KCI-MOH1 cell line-derived SCID mouse xenograft model was used for efficacy evaluation of bryostatin 1, auristatin-PE, spongistatin 1, and gemcitabine alone and in combination. Tumor growth inhibition (T/C expressed as percentage), tumor growth delay (T - C), and log 10 kill for these agents were 38%, 22 days, and 0.53; 15%, 30 days, and 0.80; 24%, 25 days, and 0.66; and 10%, 33 days, and 0.90, respectively. When given in combination, two of seven gemcitabine + auristatin-PE-treated animals were free of tumors for 150 days and were considered cured. Animals treated with a combination of bryostatin 1 and gemcitabine and a combination of spongistatin and gemcitabine produced remissions in only one of seven mice. From these results, we conclude that (a) this is the first study illustrating that clonal characteristics of primary pancreatic tumors remained unchanged when implanted in mice and as a permanent cell line grown in vitro; and (b) there is a synergistic effect between gemcitabine and selected marine products tested in this study, which is more apparent in the gemcitabine and auristatin-PE combination. The results of this preliminary study suggest that these agents should be explored clinically in the treatment of pancreatic cancer.
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PMID:Clonal preservation of human pancreatic cell line derived from primary pancreatic adenocarcinoma. 1054 95

Lung carcinoma with sarcomatous transformation (LCST) is highly aggressive and characterized by local invasion and/or distant metastasis, which leads to a shorter survival than ordinary lung carcinomas. Therefore, to elucidate whether the malignant potential of the spindle cell element in LCST is associated with the alteration of the p53 gene, four cases were examined by analyses of overexpression of the p53 oncoprotein, mutation of the p53 gene and loss-of-heterozygosity (LOH) at chromosome 17p. In two cases overexpression of the p53 oncoprotein of the spindle cell component showed a higher degree of staining than that of the carcinoma component; LOH was identified in both carcinoma and sarcomatous components in one case, while in contrast, another case showed LOH in the sarcomatous component only. Mutations were clearly detected in two cases; one showed a CTT to CGT transversion in codon 194 of exon 6 in both components, whereas the other showed a CTG to CAG transversion in codon 265 of exon 8 in the sarcomatous component only. On the basis of these observations, it suggested that the sarcomatous component shows a higher frequency of p53 gene abnormalities in comparison to the carcinoma component. These results also suggested that the acquisition of malignant potential in the sarcomatous component, or the morphological alteration of carcinoma cells, is correlated with abnormalities associated with the p53 gene.
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PMID:Alteration of the p53 gene of lung carcinomas with sarcomatous transformation (spindle cell carcinoma): analysis of four cases. 1084 48

Only a few human malignant peripheral nerve sheath tumour (MPNST)-cell lines have been reported, and their characteristics have not been fully established. In this study, we established a new human cell line, HS-Sch-2, from an MPNST of the ordinary type which arose in a 54-year-old woman without von Recklinghausen's disease. This cell line was characterized by chromosome analysis, immunohistochemistry, ultrastructural examination, and direct sequencing of the p53 gene. The HS-Sch-2 cells have grown for more than 48 months in vitro, and exhibited hypotriploid karyotypes with complex chromosome abnormalities lacking a specific pattern. Histological features of the heterotranplanted nude mouse tumours were essentially the same as those of the original MPNST, with positive reactions for S-100 protein and neuron-specific enolase but not for epithelial membrane antigen, fibronectin or CD34. Ultrastructural examination in vivo revealed intricate interdigitation of long cytoplasmic processes and basal lamina-like structures. In addition, direct sequencing of the p53 gene detected a point mutation from CGT to CAT at codon 273 in exon 8. This HS-Sch-2 cell line, which exhibits distinctive morphological characteristics of MPNST and a p53 point mutation, will be useful for biological and pathological investigations of MPNST.
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PMID:A new human malignant peripheral nerve sheath tumour-cell line, HS-sch-2, harbouring p53 point mutation. 1089 46

We performed dual (two-color) fluorescence in situ hybridization (FISH) using direct fluorescent labeling probes for p53 and chromosome 17 in six gastrointestinal (3 stomach and 3 colon) cancers. In three of these (1 stomach and 2 colon) the interphase cell nuclei showed an imbalance of signals for the p53 and chromosome 17; that is, the p53 signal count was lower than the chromosome 17 signal count, indicating deletion of the p53 gene. Moreover, metaphase FISH analysis demonstrated that those nuclei actually had a chromosome 17 with deletion of the p53 gene. Interestingly, these three cases had an abnormal chromosome 17 copy number, that is, chromosome 17 aneusomy. Furthermore, to investigate the possibility of p53 mutation in tumors with an imbalance of signals for chromosome 17 and p53 per nucleus, we performed a GeneChip p53 assay which has recently been developed. GeneChip p53 assay demonstrated that a primary tumor sample from one colon cancer case had a heterozygous point mutation of CGT (Arg) to CAT (His) at codon 273 in exon 8. In addition, a sample of metastatic tumor in the liver from the same case revealed two heterozygous point mutations. One of them was the same mutation as that is the primary tumor; the other was GTG (Val) to GGG (Gly) at codon 217 in exon 6. In conclusion, we found that the combination of dual-color FISH and GeneChip p53 assay offered reliable results and important information concerning not only deletion of the p53 gene and chromosome 17 aneusomy but also p53 mutations. Using these techniques, we demonstrated that an imbalance of signals for chromosome 17 and p53 per nucleus, chromosome 17 aneusomy, and accumulation of p53 mutations had occurred during carcinogenesis and development of gastrointestinal cancers.
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PMID:Detection of aberrations of 17p and p53 gene in gastrointestinal cancers by dual (two-color) fluorescence in situ hybridization and GeneChip p53 assay. 1095 39

Loss of p53 function has been implicated in a wide variety of human malignacies. Many studies suggest that in cervical carcinoma p53 function is inactivated either by gene mutation or by complex formation with E6 oncoprotein product of high-risk human papillomavirus (HPV). The aim of this study was to determine the status of HPV infection and p53 gene mutation as well as their correlation in cervical carcinomas. Formalin-fixed paraffin-embedded tissues of 12 cervicitis, 21 cervical intraepithelial neoplasia grade 3 (CIN 3) and 17 squamous cell carcinomas were determined for the presence of HPV using polymerase chain reaction (PCR) amplification and dot blot hybridization. The status of p53 mutations in exons 5-8 was evaluated by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) and confirmed by direct nucleotide sequencing. HPV infections were detected in all CIN 3 and squamous cell carcinomas (100%). Mutations of p53 were present in 3 of 38 HPV-positive samples: one with an ATG-->TTG transversion (Met-->Leu) in codon 237 of exon 7; and the others with a TGC-->TGG transversion (Cys-->Trp) in codon 242 of exon 7, and a CGT-->CCT transversion (Arg-->Pro) in codon 273 of exon 8, respectively. Our findings show that the frequency of p53 mutation is low in primary cervical carcinoma and that the p53 gene mutation and HPV infection are not mutually exclusive events in the development of cervical cancer. Thus, other genetic events independent of p53 inactivation may also significantly contribute to the carcinogenesis of the uterine cervix.
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PMID:p53 status and human papillomavirus infection in Thai women with cervical carcinoma. 1102 67

Although characterized by a highly variable phenotype and multiple genetic alterations, glioblastomas are considered monoclonal in origin. We here report on a 64-yr-old patient who developed a second glioblastoma in the left frontal lobe 10 yr after surgical resection of a glioblastoma of right frontal lobe. The first tumor contained 2 p53 mutations, in codon 213 (CGA-->TGA, Arg-->stop) and codon 306 (CGA-->TGA, Arg-->stop), further, 1 missense PTEN mutation (codon 257, TTC-->TTA, Phe-->Leu) and a silent PTEN mutation (codon 154, TTC-->TTT, Phe-->Phe). The second glioblastoma also contained multiple, but different mutations: p53 mutations in codons 158 (CGC-->CAC, Arg-->His) and 273 (CGT-->TGT, Arg-->Cys), and a PTEN mutation in codon 233 (CGA-->TGA, Arg-->Stop). Both neoplasms had a homozygous p16 deletion. The discordant pattern of mutations indicates that the second glioblastoma was not a recurrence but an independent second glioblastoma. The presence in these neoplasms of multiple mutations in tumor suppressor genes suggests the involvement of a novel disease mechanism but there was no indication of a DNA mismatch repair deficiency or of an inherited tumor syndrome.
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PMID:Second primary glioblastoma. 1127 8

Tumor multicentricity is occasionally observed in esophageal squamous cell carcinoma (SCC). We studied five surgically resected superficial multifocal esophageal SCCs for p53 gene mutation and genetic instability, using DNA extracted from microdissected areas. A total of 38 target areas (TAs) were analyzed in SCC, dysplasia, basal cell hyperplasia (BCH) and normal squamous epithelium. Analysis of the replication error (RER) at 10 microsatellite loci showed microsatellite instability in all TAs, as well as in normal squamous epithelium. p53 gene mutation was identified in 28.9% (11/38 TAs). All cases showed a common missense mutation in exon 8 at codon 273 (CGT-->CAT, Arg-->His), which was DNA contact mutation in the S10 beta strand. In association with microsatellite alterations, 7 of 9 TAs with p53 mutation in exon 8 at codon 273 also showed loss of heterozygosity (LOH) of p53 gene. LOH of p53 gene was detected in 83.8% (31/37 TAs). LOH at D2S123 on 2p16 near MSH2 gene and at D3S1611 on 3p22 near MLH1 gene was detected in 65.4% (17/26) and 71.4% (10/14) TAs, respectively. Frequencies of LOH at p53 and D2S123 were similar in non-cancerous areas and SCCs. LOH of p53 and D2S123 were found in 50% (5/10 TAs) of non-cancerous areas and 60% (9/15 TAs) of SCCs. Our results suggest that genetic instability induces esophageal tumor multicentricity, and that p53 gene contact mutation together with LOH are early events of the multistage carcinogenesis of multifocal primary esophageal SCC.
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PMID:p53 Gene mutation and genetic instability in superficial multifocal esophageal squamous cell carcinoma. 1189 9


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