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)

Bat lung (BAT(2)CL6) cells infected with bovine leukemia virus (BLV) cause malignant tumors in nude mice that after 6 weeks subcutaneous growth, have an average volume of 0.3m(3). Uninfected bat lung cells (Tb 1 Lu) produce small benign neoplasms that average 0.003 cm(3). BAT(2)CL6 cells were transfected in vitro with expression vectors that produce wild type human or mutant p53. Production of human p53 in transfected BAT(2)CL6 cells was confirmed by immunoprecipitation of p53 and by immunohistochemical staining using anti-human p53 monoclonal antibodies. BAT(2)CL6 cells transfected with wild type p53 produced tumors in nude mice averaging 0.03 cm(3) whereas cells transfected with mutant p53 yielded tumors averaging 0.3cm(3). BAT(2)CL6 cell tumors after 1 week subcutaneous growth were transfected in situ with the wild type p53 gene. At 6 weeks tumor volume of in situ transfected tumors was similar to those resulting from cells transfected in vitro. Histopathologic examination and immunochemical staining of tumors produced in nude mice after wild type p53 treatment showed no significant differences when compared to tumors produced by untreated BAT(2)CL6 cells. Therefore, it is likely that the tumors produced by p53 treated-cells arose from cells that escaped transfection. The reduction of tumor size by restoration of wild type 53 may prove to be a useful therapy for BLV-induced tumors.
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PMID:Wild type p53 reduces the size of tumors caused by bovine leukemia virus-infected cells. 862 74

The replication error phenotype (RER+) represents an important new form of genetic alteration characterized by widespread instability in repetitive nucleotide sequences. The aim of this study was to compare the features of RER+ gastric tumours with those of RER+ colonic tumours. RER status was determined by analysis of size alterations in the BAT-26 mononucleotide repeat microsatellite. Twelve of 121 (10 per cent) gastric carcinomas from a low-incidence region were found to be RER+. BAT-26 instability was associated with tumours showing an absence of nodal invasion ( p=0.009) and with a trend for improved prognosis. These tumours were more frequent in older, female patients. Frameshift mutations in mononucleotide repeat sequences within the transforming growth factor-beta receptor II (RII), insulin-like growth factor II receptor (IGFIIR), and BAX genes were observed in 83, 33, and 25 per cent, respectively, of RER+ tumours. Only 1/12 (8 per cent) RER+ tumours contained a p53 gene mutation compared with 29/109 (27 per cent) RER- tumours. RER+ gastric carcinomas therefore share several important features with RER+ colonic tumours, including less frequent nodal invasion, improved prognosis, a similar frequency of mutation in growth control genes containing repetitive nucleotide sequences, and a low frequency of mutation of the p53 tumour suppressor gene.
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PMID:Gastric carcinomas with microsatellite instability: clinical features and mutations to the TGF-beta type II receptor, IGFII receptor, and BAX genes. 1039 2

Microsatellite instability (MSI) has been reported to occur in a wide variety of sporadic tumours, such as colorectal and gastric cancers. MSI positivity has been associated with a particular clinico-pathologic profile, including the presence of abundant lymphoid infiltration, poor differentiation and a relatively good outcome for the patients. Since medullary breast carcinomas (MBCs) share these clinico-pathologic features with the MSI-positive tumours described above, we evaluated MSI in this particular histologic type of breast cancer. DNA of 24 MBC cases was extracted from formalin-fixed, paraffin-embedded tissue. The presence of MSI was analysed using BAT-26. We also searched mutations in 2 target genes: TGF-beta RII and BAX. Five cases of the series were also analysed for 1 (CA) dinucleotide tandem repeat sequence (D1S158), 8 tetranucleotide repeat sequences (D3S1358, D5S818, D7S820, D8S1179, D13S317, D21S11, FGA and VWA) and 1 pentanucleotide repeat (dAAAAT), localized in intron 1 of p53 gene. We found 2 carcinomas (8.3%) with BAT-26 instability. None of the cases had mutations in the "target genes", TGF-beta RII and BAX, including the 2 cases with BAT-26 instability. No MSI was observed using the panel of tetra- and pentanucleotide markers. Loss of heterozygosity was found in some loci. No significant difference in mean MIB-1 index according to RER status was observed. The low frequency of MSI in MBC is similar to that of other histologic types of breast cancer. Although MBCs share some clinico-pathologic features with colorectal and gastric carcinomas, which exhibit a high frequency of MSI, the underlying genetic events leading to this breast tumour are different from those leading to tumours of the digestive tract.
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PMID:Microsatellite instability in medullary breast carcinomas. 1041 60

We have studied 27 hepatocellular carcinomas (HCCs) to identify possible relationships between microsatellite instability (MSI), p53 mutations, and HBV infection in hepatocarcinogenesis. MSI was assessed using 19 polymorphic markers and the poly(A) tract BAT-26. All coding regions of p53 were examined for mutations. Tumors were also examined for presence of hepatitis B virus (HBV) DNA sequences; 66.6% of the samples exhibit MSI in at least one microsatellite locus and 44% in two or three loci. None of the tumors examined showed alterations in BAT-26. Moreover, 73.3% of samples with indication of HBV infection showed instability in at least one marker. No association between MSI and pathological profile was found. Five (18.5%) samples harbored mutations in p53, three missense, and two insertions, all in exons 5 and 8 not previously reported. No mutations were detected in codon 249, which has been linked with dietary intake of aflatoxins. Our results support the hypothesis that HCC is a "low" MSI tumor. Only 1/5 samples with MSI in more than two markers harbored a mutation in p53. Although the number of samples is too small to support a statistical significance, this finding may indicate an inverse relationship between p53 mutations and MSI in HCC.
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PMID:Microsatellite instability and p53 mutations in hepatocellular carcinoma. 1066 91

Microsatellite markers may provide evidence of faulty DNA mismatch repair (MMR) via the detection of microsatellite instability (MSI). The choice of microsatellite markers may impact on the MSI detection rate. In hereditary non-polyposis colon cancer (HNPCC), several informative microsatellite markers have been recommended. Two of these, BAT 25 and BAT 26, are quasi-homozygous, enabling analysis of tumour DNA in the absence of paired normal DNA. Sixty-six breast cancer patients under 45 years of age at diagnosis were examined for MSI at BAT 25 and BAT 26. Tumour DNA was extracted from paraffin-embedded tissue. No MSI was detected at the BAT 25 or BAT 26 loci. An additional five microsatellite markers, known to be informative for HNPCC, were examined for MSI in these patients. Apparently-normal profiles were achieved. A tabulated survey of 306 microsatellite markers used to detect MSI in breast cancer revealed that only 35.5% of markers detected MSI at an average rate of 2.9%. The MSI detection rate at the specific HNPCC markers varied from 0% to 10% in breast cancer, with D175250 and TP53 being the HNPCC markers most suitable for analysis of breast cancer. The size of the microsatellite marker's repeat unit did not impact on MSI detection rates. Compiled data from large studies (n > 100) revealed D115988 as the marker with the highest MSI detection rate. Genomic instability pathways of carcinogenesis, characterised by MMR defects and MSI, appear to play a role in the genesis of some breast cancer types.
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PMID:Microsatellite instability markers in breast cancer: a review and study showing MSI was not detected at 'BAT 25' and 'BAT 26' microsatellite markers in early-onset breast cancer. 1084 76

The short arm of chromosome 3 is thought to harbor a novel oncogenic locus that is important in the genesis of lung cancer. The region at 3p21 is believed to contain a distinct locus that is sensitive to loss from the action of tobacco smoke carcinogens and has been reported to be specifically targeted for deletion in lung cancer. To investigate whether 3p21 alteration in lung cancer is associated with carcinogen exposure, PCR-based analysis was performed to detect loss of heterozygosity (LOH) on chromosome 3 at 3p21 in non-small cell lung carcinoma (NSCLC). We also measured instability at the BAT-26 locus, because the mismatch DNA repair gene, hMLH1, is found at 3p21. LOH at 3p21 was analyzed for association with the clinical features of NSCLC, p53 mutation status, polynuclear aromatic hydrocarbon-DNA adduct levels (measured using 32P-postlabeling) and carcinogen exposure information including cigarette smoking and asbestos exposure. Of 219 lung cancers, 150 cases (68.5%) were informative at the D3S1478 locus, and 44.2% of squamous cell carcinoma cases and 30.2% of adenocarcinoma cases showed 3p21 LOH. None of the cancers showed BAT-26 instability. The prevalence of 3p21 LOH was higher in both current and former smokers compared with never smokers and was higher in p53 mutated cases. Among squamous cell carcinoma cases, there was a strong association of increased 3p21 LOH with increasing polynuclear aromatic hydrocarbon-DNA adducts levels (P = 0.03), as well as an increased prevalence LOH with earlier age of smoking initiation (P = 0.02). Our results confirm that 3p21 LOH is strongly associated with measures of biologically effective dose of exposure to tobacco carcinogens. Our results also suggest that alterations of hMLH1 are not related to any of the reported associations, because there was no evidence of microsatellite instability. Finally, LOH in 3p21 may be an early molecular event in NSCLC, because it is significantly associated with a tendency to start smoking at a young age.
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PMID:Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3p21 in lung cancer. 1121 58

Despite low radiation dose rates, radioimmunotherapy (RIT) has proven particularly effective in the treatment of malignancies, such as lymphoma. Apoptosis has been suggested to be a major mechanism for cell death from continuous low-dose rate radiation from radioimmunotherapy. The goal of this study was to examine Raji lymphoma xenografts for induction of apoptosis and modulation of apoptosis-related gene and protein expression in response to 67Cu-2IT-BAT-Lym-1 RIT. In preclinical and clinical trials, 67Cu-2IT-BAT-Lym-1 has shown an exceptionally long tumor residence time associated with substantial cumulated radiation doses. The Raji model mirrors human lymphomas that have mutant p53 and increased BCL2 expression. Untreated athymic BALB/c nu/nu mice and mice treated with 400 micrograms Lym-1, or 335-500 microCi 67Cu on less than 400 micrograms Lym-1 antibody, were observed for toxicity and response over 84 days. Subgroups of 4-5 mice were sacrificed at 3, 6 and 24 h after therapy so that tumors could be examined for poly(ADP-ribose) polymerase (PARP) and DNA ladder evidence for apoptosis and for BCL2, p53, p21, GADD45, TGF-beta 1 and c-MYC gene and protein expression. Untreated tumors had little evidence of apoptosis and Lym-1 had no effect on apoptosis or gene expression. 67Cu-2IT-BAT-Lym-1 RIT induced an overall response rate of 50% with tolerable toxicity, and 29% of the tumors were cured at cumulated tumor radiation doses of about 1800 cGy. Apoptosis was greatly increased in the RIT treated Raji xenografts as evidenced by cleavage of PARP to the characteristic 85 kD fragment at 3 and 6 h and by the DNA cleavage pattern. BCL2 gene and protein expression were substantially decreased at 3 and 24 h, respectively, after 67Cu-2IT-BAT-Lym-1 RIT despite only modest cumulated radiation doses (56 cGy at 3 h). Evidence for apoptosis preceded tumor regression by 4-6 days. In these therapy-resistant, human lymphoma tumors treated with 67Cu-2IT-BAT-Lym-1, apoptosis was convincingly demonstrated to be a major mechanism for the effectiveness of RIT and occurred by p53-independent mechanisms.
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PMID:Apoptosis-related gene and protein expression in human lymphoma xenografts (Raji) after low dose rate radiation using 67Cu-2IT-BAT-Lym-1 radioimmunotherapy. 1147 86

Microsatellite instability (MSI) is a hallmark of the DNA mismatch repair deficiency that is one of the pathways of gastric carcinogenesis. Clinicopathologic characteristics of MSI+ gastric cancers remain unclear. To determine the correlation between MSI status and clinical features, we analyzed 327 consecutive gastric cancers for the occurrence of MSI in the BAT-26 marker. Because it has been proven that MSI at BAT-26 reflects the MSI+ phenotype, cancers with alteration at BAT-26 were categorized as having the MSI+ phenotype. The expressions of hMLH1, hMSH2, p53, MUC1, MUC2, and CEA were evaluated immunohistochemically using the tissue array method. The MSI+ phenotype was found in 9.5% (31/327) of gastric cancers examined. MSI+ gastric cancers were significantly associated with older age, antral location, Borrmann's gross Type II, intestinal subtype, lower prevalence of lymph node metastasis, and lower pTNM stage (P <.05). By multivariate logistic regression, MSI+ gastric cancers had a lower prevalence of lymph node metastasis independent of tumor invasion (P <.001). MSI+ gastric cancers displayed frequent frameshift mutations of transforming growth factor-beta type II receptor (90.3%), BAX (61.3%), hMSH3 (38.7%), and E2F4 (61.3%) genes and diminished hMLH1 (24/31) or hMSH2 (4/31) expressions. The MSI+ phenotype correlated with patient survival in advanced gastric carcinoma (P =.046). In conclusion, MSI+ phenotype in gastric cancers was found to have distinct clinicopathologic characteristics and to be predictive of a favorable outcome in advanced carcinoma.
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PMID:Distinct clinical features and outcomes of gastric cancers with microsatellite instability. 1206 77

To investigate the potential implication of the subtype of intestinal metaplasia in the progression to the gastric carcinoma, we analyzed the mutations of the p53 gene and microsatellite instability (MSI) both in the complete type (type I) and in the sulphomucin-secreting incomplete type (type III) intestinal metaplasia located adjacent to the gastric carcinoma. p53 mutations were observed in 13.3% of type I, in 6.6% of type III intestinal metaplasia, and in 40% of gastric carcinoma. The difference between p53 mutations observed in type I and type III intestinal metaplasia was not statistically significant. No identical mutation of the p53 gene was found in the intestinal metaplasia and carcinoma specimens from the patients. There was no case of intestinal metaplasia showing MSI. In gastric carcinomas, MSI was observed in six cases (40%). The cases harboring BAT-26 instability did not have the mutation of the p53 gene. These data suggest that intestinal metaplasia adjacent to gastric carcinoma, irrespective of its subtype, do not have the genetic alterations as showing in their carcinoma tissues.
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PMID:p53 mutations and microsatellite instabilities in the subtype of intestinal metaplasia of the stomach. 1217 44

The influence of MSI on treatment outcome of colorectal cancers remains unclear and deserves further investigation. We recruited 244 patients with stage IV sporadic colorectal cancers for our study, based on appropriate eligibility criteria. Patients were nonrandomly allocated to 2 treatment groups of either with or without high-dose 5-FU plus leucovorin chemotherapy (HDFL, 5-FU 2,600 mg/m(2) leucovorin 300 mg/m(2) maximum 500 mg). Each treatment group was further divided into 2 subgroups according to high-frequency MSI (MSI-H) status. MSI-H was defined as the appearance of MSI in at least 2 of the 5 examined chromosomal loci (BAT-25, BAT-26, D5S346, D2S123, D17S250). We compared clinicopathologic parameters, p53 overexpression and overall survival between the groups. In addition, 4 subgroups were identified as follows: MSI-H(+)HDFL(+), n = 35; MSI-H(-)HDFL(+), n = 134; MSI-H(+)HDFL(-), n = 17; MSI-H(-)HDFL(-), n = 58. There was no significant difference of background clinicopathologic data between the HDFL(+) and HDFL(-) treatment groups (p > 0.05). Survival analyses indicated that the patients of subgroup MSI-H(+)HDFL(+) survived significantly longer than those of subgroup MSI-H(-)HDFL(+), with median survival times of 24 (95% CI 20.2-27.9) and 13 (95% CI 11.6-14.4) months, respectively (p = 0.0001, log-rank test). In contrast, in patients without chemotherapy, the prognosis was poor irrespective of MSI status, with median survival times of 7.0 (95% CI 4.6-9.4) and 7.0 (95% CI 6.1-7.9) months in the MSI-H(+)HDFL(-) and MSI-H(-)HDFL(-) subgroups, respectively (p = 0.8205, log-rank test). MSI-H cancers responded significantly better to HDFL (p = 0.001), with a mean response rate of 65.71% (95% CI 49.98-81.44%) in subgroup MSI-H(+)HDFL(+) compared to 35.07% (95% CI 26.99-43.15%) in subgroup MSI-H(-)HDFL(+). There appeared to be no preferential metastatic site where response to HDFL can be predicted based on the MSI status of the primary tumor. Toxicity to HDFL was similarly minimal between MSI-H(+) and MSI-H(-) patients (p > 0.05). Multivariate analysis of all patients further indicated that MSI-H and chemotherapy were independent favorable prognostic parameters (p < 0.05). Thus, the better prognosis of stage IV sporadic colorectal cancers with MSI-H may be associated with better chemosensitivity, rather than lower aggressiveness in biologic behavior.
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PMID:High-frequency microsatellite instability predicts better chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection. 1223 91


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