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)

Karyotype and fluorescence in situ hybridization analyses have demonstrated the frequent presence of an altered static state of the number of chromosomes (ie, aneuploidy) in lung cancer, but it has not been directly established whether aneuploidy is in fact associated with a persistent increase in the rate of chromosomal losses and gains (ie, chromosome instability, or CIN). The study presented here used a panel of 10 lung cancer cell lines to provide for the first time direct evidence that CIN is a common feature in lung cancer cell lines in association with the presence of significant aneuploidy. In addition, we found that the CIN phenotype correlates well with the presence of p53 mutations. However, human papilloma virus 16-E6-directed inactivation of p53 in a representative non-CIN lung cancer cell line did not result in the induction of CIN, at least up to the 25th generation, suggesting that inactivation of p53 itself is unlikely to directly induce CIN in lung cancer cells. Interestingly, however, significant CIN could be induced in conjunction with the generation of aneuploid populations when the mitotic spindle formation was transiently abrogated in p53-inactivated cells. These results suggest that inactivation of p53 may allow lung cancer cells to go through an inappropriate second division cycle under certain forms of mitotic stresses, which would result in the induction of the CIN phenotype in conjunction with the generation of aneuploidy.
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PMID:Persistent increase in chromosome instability in lung cancer: possible indirect involvement of p53 inactivation. 1158 62

Association of infection with papillomavirus and dysplasia of the cervix uteri has been firmly established. There are only few cervical cancers where no HPV DNA is detectable. The mechanism of epithelial cell immortalization by interaction with tumour suppressor genes p53 and pRb by viral oncogenes E6 and E7 is elucidated. Progression of the HPV infected cell to a malignant phenotype involves further modification of host gene expression and/or mutations. The appearance of chromosomal aberrations can lead to mutational inactivation or loss of tumour suppressor genes (TSG), activation and amplification of oncogenes, with importance for the process of carcinogenesis. Oncogene amplification, with exception of few reports, seems not to be a major mechanism in cervical carcinogenesis. In contrast, cytogenetic and loss of heterozygosity (LOH) results from CIN and invasive cancer demonstrate alterations at specific chromosomal regions, pointing at localisation of TSG. Genetic alterations at chromosomes 3p, 6p, 1lq were frequently found early in tumour development Primary invasive carcinoma showed additional allelic losses at chromosome arms 6q, 17p and 18q. Useful biological diagnostic and prognostic markers for high-risk HPV infection and malignant progression may be p16NK4 p27Kip, and NET-I/C4.8. Putative senescence genes relevant for HPV-induced carcinogenesis are localized on chromosomes 2, 4 and 10. Genes for Telomerase suppression are presumably located on chromosomes 3, 4 and 6. Natural immune responses to HPV infection exist Therefore, immune therapy is an attractive possibility for prevention and therapy of HPV infection. To date, vaccine development has reached clinical evaluation. Prophylaxis aims at the induction of virus neutralizing antibodies to capsid proteins. Virus-like particle vaccines are currently tested in clinical trials. Due to the long lag period between infection and clinical manifestation trials will take a long time until conclusive results are obtained. Mandatory expression of viral and perhaps certain cellular genes in infected epithelial and tumour cells offers targets for therapeutic approaches. Since most dysplasia clears spontaneously the viral infection is immunogenic to some extent. However, in some individuals the immune response has to be stimulated by vaccination in order to be effective. Several strategies are being tested in clinical trials and others are in preclinical development The task will be to circumvent immunosuppressive features of the HPV infected cells.
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PMID:HPV induced cervical carcinogenesis: molecular basis and vaccine development. 1279 44

To determine the prevalence of gastric precancerous lesions and mucosal genetic alterations in relatives of a cluster of familial gastric cancer (FGC), we studied a kindred spanning two generations. The founder, daughter and niece underwent surgery for gastric cancer (GC); a son and other two daughters of the founder, presented with chronic dyspepsia. In all subjects, gastric mucosa samples were analysed for pathological features, Helicobacter pylori infection, microsatellite (MIN) and chromosomal (CIN) instability. The overexpression of mp53 and c-myc, and cytoplasmic beta-catenin delocalisation were found in the 2 younger cancer patients. All GC and gastritis patients had normal E-cadherin expression and were MIN-negative. Aneuploidy characterised all GC cases, and mixed euploid and aneuploid cell populations were present in the gastric biopsies from two of three 'at-risk' relatives. These two subjects, one of whom had severe active gastritis, and gastric mp53 and c-myc expression, were CagA-positive H. pylori-infected. DNA aneuploidy, p53 and c-myc expression disappeared after H. pylori eradication. In this FGC cluster, genetic abnormalities were found in first-degree relatives (3 patients) only in presence of H. pylori infection (2 cases H. pylori-positive versus 1 case H. pylori-negative) supporting the hypothesis that, besides the influence of a genetic profile, FGC may be, at least partly, mediated by intrafamilial clustering of H. pylori infection.
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PMID:Is there a link between environmental factors and a genetic predisposition to cancer? A lesson from a familial cluster of gastric cancers. 1285 70

Most colorectal cancers display chromosomal instability, which is characterized by gross chromosomal rearrangements, loss of heterozygosity and aneuploidy. We have previously demonstrated a link between JC virus strains Mad-1 and Delta98 and colorectal cancer. Others have also associated the virus to the induction of colon cancer and aneuploid brain tumors by producing a highly tumorigenic protein named T antigen (TAg), which binds to beta-catenin and inactivates key proteins such as p53. The aim is to demonstrate that JC virus is capable of inducing chromosomal instability in colonic cells. We used the human colon cancer cell line RKO as a model. The cell line has wild-type p53, wild-type beta-catenin and APC and is diploid. Neuroblastoma JCI cells, which are infected with the virus, VA13 fibroblasts, which are transformed by the SV40 TAg, were used as positive controls. HCT116, which has mutated beta-catenin, and SW480, which is a model of CIN, were also used as controls. The genomes of the Mad-1 and Delta98 strains were transfected into cells. As negative controls we used pUC or no plasmids. Cells were collected at 0, 7, 14, and 21 days after transfection. PCR was used for the detection of TAg and the regulatory region DNA sequences at different time frames and Southern blot of whole genomic extracts for viral DNA integration into the host genome. Immunofluorescence and Western blot were performed for TAg, viral capsid proteins, and nuclear beta-catenin expressions, whereas coimmunoprecipitation was used to detect protein interactions. Karyotype analysis and electron microscopy were performed to seek chromosomal instability and cell abnormalities, respectively. Retention of viral sequences was observed for Mad-1- and Delta98-transfected RKO cells at all time frames with PCR only, whereas Southern blot analysis showed nonintegrated sequences at T7 alone. TAg and capsid protein expressions, as well as increased p53 and nuclear beta-catenin, were observed between T0 and T7 for Mad-1 and Delta98 alone. Also, interaction between TAg and both p53 and beta-catenin was also observed between T0 and T7. Chromosomal instability, characterized by chromosomal breakage, dicentric chromosomes, and increasing ploidy, was observed at all time frames for Mad-1 and Delta98, as well as cell abnormalities. In conclusion, we demonstrate that JC virus Mad-1 and Delta98 are able to induce chromosomal instability in colonic cells with a hit and run mechanism that involves an early interaction with beta-catenin and p53.
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PMID:Induction of chromosomal instability in colonic cells by the human polyomavirus JC virus. 1461 21

Colorectal carcinomas develop according to particular genetic pathways, including the chromosomal instability (CIN+), microsatellite instability (MSI+) and MSI- CIN- routes. We have determined the genetic pathway in patients with MYH-associated polyposis (MAP), a syndrome of colorectal adenomas and cancer that results from defective base excision repair (BER). As in previous studies, MAP tumors showed a high frequency of G>T mutations in APC, in accordance with defective BER. We found that K-ras mutations were common in MAP tumors, all of the changes comprising conversion of the first guanine residue of codon 12 to thymidine (G12C, GGT>TGT). We found no BRAF mutations at the codon 599 hotspot or elsewhere in exon 14. Almost all of the MAP cancers were near-diploid (CIN-), and none was MSI+. A few p53 mutations were found, but these were not predominantly G>T changes. p53 overexpression was, however, frequent. No SMAD4 or TGFBIIR mutations were found. MAP tumors appear to follow a distinct genetic pathway, with some features of both the CIN and MSI pathways. BER deficiency is rarely accompanied by CIN or MSI. The spectrum of somatic mutations in MAP tumors reflects both selection and hypermutation to which certain guanine residues are particularly prone.
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PMID:Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. 1463 73

The aim of this study was to investigate pRb2/p130, p107 and p53 expressions in precancerous lesions and squamous cell carcinoma (SCC) of the uterine cervix. We evaluated Human Papillomavirus (HPV) testing and typing and pRb2/p130, p107 and p53 expressions (antibody D07) of 48 patients showing low-grade cervical intraepithelial neoplasia (LCIN, 18 cases), high-grade CIN (HCIN, 13 cases) and SCC (17 cases). Paraffin-embedded tissue sections were analyzed for the study. High-risk HPV types were present in 67%, 89% and in 100% of HPV-positive LCIN, HCIN and SCC, respectively (Spearman's correlation coefficient: 0.393, p=0.035). Positive pRb2/p130 expression was detected in 89% of LCIN, 77% of HCIN and in 35% of SCC (p=0.001), whereas diffuse p107 expression was 72%, 62% and 100%, respectively (p=0.024). The results of p53 expression in CINs and SCCs showed values (not statistically significant) comparable with the literature data concerning the antibody D07. For the first time, we tested pRb2/p130 and p107 expressions in CINs and SCCs. We found a progressive decrease in pRb2 expression from CINs to SCCs that suggests an important role of pRb2 in cervical carcinogenesis. Indeed, p107 expression does not seem to be a useful factor. In our opinion, confirmed by the literature data, p53 immunostaining helps to biologically characterize CIN (in particular LCIN) when each case is evaluated separately considering HPV testing/typing.
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PMID:PRb2/p130, p107 and p53 expression in precancerous lesions and squamous cell carcinoma of the uterine cervix. 1615 62

In the carcinogenesis of colorectal cancer (CRC) genetic instability and dysfunction of the Wnt-signalling pathway play important roles. Most Wnt-signalling dysfunctions lead to the nuclear accumulation of beta-catenin. The aim of the present study was to investigate whether nuclear accumulation of beta-catenin is associated with prognosis and genetic instability. We used immunohistochemistry to study nuclear beta-catenin expression in 67 CRCs. The expression was evaluated in the entire tumour section as mean values and in tumour budding at the invasive margin. We compared the results with chromosomal and microsatellite instability (CIN vs. MSI), p53 accumulation, and clinicopathological variables including survival. The nuclear accumulation of beta-catenin was significantly associated with abnormal p53 expression and aneuploidy, typically for CIN, whereas no tumour with nuclear beta-catenin expression at the invasive margin displayed MSI. The beta-catenin expression pattern did not correlate significantly with CRC patient prognosis when including all stages. However, in the clinically most interesting prognostic group, Dukes' stage B patients, high nuclear accumulation of beta-catenin was associated with a poor prognosis (p=0.01). Our results suggest that nuclear accumulation of beta-catenin in CRC is related to CIN and may be of prognostic importance. However, larger studies are needed to verify these findings.
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PMID:Beta-catenin expression in relation to genetic instability and prognosis in colorectal cancer. 1720 86

Infection with high risk papilloma viruses (HPV types 16, 18, and relative ones) initiates the development and progression of uterine neck cancer. The viral genome is found in pre-tumorous lesions (stage I to III intraepithelial neoplasias--CIN) and carcinomas, persisting in cells in episomal or integrated state. In all tumors, there is the expression of two viral transforming genes, E6 and E7, the main function of which is the inactivation of genes that suppress tumoral growth, p53 and retinoblastoma gene. In CIN and carcinomas, losses of heterozygosity are found in various chromosomes, mainly in the areas of suppressor genes; some of them can be specific for certain stages of the malignant process. Among epigenetic alterations, the main significance for the progress of the disease belongs to the methylation of the promoter areas of the genes involved in the process of cell division, which may be specific for each separate tumor and appears in approximately 30 to 40% of tumors. Another important epigenetic alteration is the increase in the expression of p16ink4a gene, which is the inhibitor of cyclin-dependent kinases; this appears at CIN I stage and may serve as an additional early diagnostic marker. Telomerase activity has been identified in all uterine neck tumors, but each tumor has its own spectrum of spliced RNA coding this enzyme. Expression microchip technique has shown that each tumor is individual according to the spectrum of "working" genes, and this spectrum varies in the process of tumor progression.
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PMID:[Genetic and epigenetic factors of cervical tumor progression]. 1808 May 24

The genomic aberration profile of chromosome 20q in distal CIN colon carcinomas was analysed using allelotyping and CGH arrays. Allelotyping revealed carcinomas with allelic imbalance along the full long arm, and carcinomas with fully non-aberrant 20q. Oligonucleotide-based CGH showed that among the carcinomas without allelic imbalance, 47% had in fact a gain. In this subgroup, quantitative PCR for the TOPI gene (20q12) confirmed this gain, and fluorescence in situ hybridization showed that the chromosome 20q gain resulted from tetra/polysomy instead of aneusomy. The 20q gain correlated with a high frequency of aberrations, with allelic imbalance at TP53 locus but not at APC locus, and carcinomas with a disomic 20q showed low frequency of genomic aberrations and were significantly associated to mucinous phenotype. The prognostic value of 20q amplification was not demonstrated in this study. These results indicate that on the basis of aberration frequency, chromosome 20q and TP53/APC locus status, distal CIN carcinomas harbor a high degree of genetic heterogeneity suggesting several pathways for carcinogenesis. This study also indicates that allelotyping needs to be carried out with a complementary technique, such as quantitative PCR.
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PMID:Evidence for various 20q status using allelotyping, CGH arrays, and quantitative PCR in distal CIN colon cancers. 1939 60

We hypothesized that in a comprehensive analysis of colorectal carcinomas (CRC) the three currently known major molecular mechanisms of carcinogenesis (i.e., chromosomal instability, microsatellite instability, and CpG island methylator phenotype, CIMP) would associate with the molecular features indicative of these pathways, allowing a molecular classification. A prospectively collected clinicopathologically well-characterized series of 130 CRCs was tested for chromosomal instability (DNA-flow cytometry and analysis of allelic imbalance with microsatellite markers 5q21, 8p21, 9q21, 17p13, and 18q21), microsatellite instability (Bethesda panel), CIMP (MethyLight), and mutations of K-ras, B-raf, APC, and p53. Morphology was reviewed, and nuclear beta-catenin translocation was assessed by immunohistochemistry. Based on the molecular features, sporadic high-degree microsatellite instable tumours, tumours of the hereditary non-polyposis coli carcinoma syndrome, and 'sporadic standard-type' CRC could be delineated (14, 4, and 55, respectively). However, overlap between classes was seen for 46 of the remaining tumours where widespread or occasional methylations (excluding MLH1) were observed, and the majority had chromosomal instability. Importantly, a group of 11 tumours was observed without either microsatellite or chromosomal instability, nor any methylation. Morphologically, these tumours were without any distinguishing features, all had tumour budding and 10 showed nuclear beta-catenin translocation. Overall, the data give an overview of the molecular classes in CRC that should be taken into account in studies on carcinogenesis and clinicopathological studies. Specifically, the absence of CIN, MSI, and CIMP in an 8.46% fraction of tumours delineates a group to be aware of.
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PMID:Chromosomally and microsatellite stable colorectal carcinomas without the CpG island methylator phenotype in a molecular classification. 1957 46


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