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)

T lymphocytes recognize their antigenic targets as peptides associated with major histocompatibility complex molecules. The HLA-A11 allele, a preferred restriction element for Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocyte responses, presents an immunodominant epitope derived from the EBV nuclear antigen 4. Subpicomolar concentrations of a synthetic nonamer peptide, IVTDFSVIK, corresponding to amino acids 416-424 of the EBV nuclear antigen 4 sequence, can sensitize phytohemagglutinin-stimulated blasts to lysis by EBV-specific HLA-A11-restricted cytotoxic T-lymphocytes. We show that micromolar concentrations of this peptide induce assembly and surface expression of HLA-A11 in an A11-transfected subline of the peptide transporter mutant cell line T2. Using the IVTDFSVIK peptide and a series of synthetic nonamer peptides, differing from the original sequence by single amino acid substitutions, we have defined a motif for HLA-A11-binding peptides. This predicts the presence of a hydrophobic amino acid in position 2, amino acids with small side chains in positions 3 and 6, and a lysine in position 9. Using this motif, we have identified a peptide in the carboxyl-terminal end of wild-type p53, ELNEALELK, which is able to induce HLA-A11 assembly as efficiently as the IVTDFSVIK viral peptide.
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PMID:An HLA-A11-specific motif in nonamer peptides derived from viral and cellular proteins. 838 18

Epstein-Barr virus (EBV) immortalized human lymphoblastoid cell lines express six virally encoded nuclear proteins, designated EBV nuclear antigens 1-6 (EBNA-1-6). We show that the EBNA-5 protein (alternatively designated EBNA-LP) that is required for B-cell transformation can form a molecular complex with the retinoblastoma (RB) and p53 tumor suppressor proteins. Using EBNA-5 deletion mutants, we have found that a 66-amino acid-long peptide, encoded by the W repeat of the EBV genome, is sufficient for binding. Point mutations of RB and p53 that inhibit their complexing with other DNA viral oncoproteins do not affect their binding to EBNA-5. p53 competes with RB for EBNA-5 binding. Our data suggest that the mechanisms involved in EBV transformation may include impairment of RB and p53 function.
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PMID:EBNA-5, an Epstein-Barr virus-encoded nuclear antigen, binds to the retinoblastoma and p53 proteins. 839 Jun 66

Epstein-Barr virus (EBV) as a member of the herpesvirus family persists lifelong in the human body and causes diseases associated with virus replication (infectious mononucleosis, oral hairy leukoplakia) as well as neoplastic conditions such as nasopharyngeal carcinoma, B-cell lymphoma, Hodgkin's disease associated with viral latency. This complex biology relates to a highly regulated control of the persisting virus. Still, EBV is lytically produced in certain compartments of the human body. Epithelial cells were found to be of key importance for this. Various routes (cell fusion, IgA receptor-mediated uptake) were described for EBV to enter epithelial cells in the absence of CR2 receptor. Viral entry into cells, however, via CR2 receptor fusion or IgA mediated was not found to be sufficient for viral production. The molecular mechanisms for the lack of viral production in most target cells are primarily the presence of silencer activities and the early elimination of cells entering the lytic cycle. Only terminally differentiated epithelial cells are capable of supporting an efficient lytic cycle of EBV replication. EBV-mediated suppression of apoptosis as well as down-regulation of cellular and viral gene products, such as HLA molecules, which mediate recognition by the immune system, are important contributing factors to the development of these neoplasias where viral genes, possibly via interaction with anti-oncogenes, such as p53, in context with genetic and environmental factors play a key role. Novel diagnostic tools and a vaccine have been developed which could help to control EBV-related diseases.
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PMID:Epstein-Barr virus and its interaction with the host. 840 48

We have analysed 22 nasopharyngeal carcinomas (NPCs) for expression of the small nuclear Epstein-Barr virus (EBV)-encoded RNAs (EBERs) and for immunohistologically detectable overexpression of p53. In situ hybridization demonstrated expression of the EBERs in 13 undifferentiated NPCs while nine squamous cell NPCs were EBER-negative. These results therefore confirm our previous DNA-DNA in situ hybridization studies and demonstrate that in the nasopharynx EBV is exclusively associated with undifferentiated but not with squamous cell carcinomas. p53 overexpression was demonstrated by immunohistology in 5 of 9 squamous cell NPCs and in 9 of 13 undifferentiated NPCs. Thus, there appears to be no correlation of p53 overexpression with EBV infection. These results are unexpected in the light of previous studies demonstrating that the p53 gene in primary undifferentiated NPC is consistently in the wild-type configuration. By contrast, analyses of squamous cell carcinomas of the head and neck have demonstrated that p53 overexpression in these cases is the result of p53 gene mutation. Whilst more detailed genetic analysis is required, our results suggest that mechanisms other than mutation of the p53 gene may be responsible for the stabilization of the protein in cases of undifferentiated NPC. It is tempting to speculate that an EBV-encoded protein may be involved.
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PMID:P53 overexpression and Epstein-Barr virus infection in undifferentiated and squamous cell nasopharyngeal carcinomas. 819 33

All Burkitt lymphoma (BL) biopsies and cell lines carry a c-myc/Ig translocation. The resulting constitutive activation of c-myc is regarded as an essential factor for the progressive growth of the tumor cells. At least 60% of BL cell lines carry a mutated p53 gene as well. It has been shown that the growth of mutant p53 carrying tumor cells could be inhibited by the introduction of wild-type p53. In order to examine whether this also applies to the presumably 'myc-driven' BL cell, we have transfected the Epstein-Barr virus (EBV) negative BL41 cell line with a temperature sensitive p53 mutant (p53-Val135) that expresses p53 with a largely mutant conformation at 37.5 degrees C and mostly wild-type conformation at 32 degrees C. At 37.5 degrees C, the p53-Val135 transfected cells behaved like the parental or neo transfected control cells. However, expression of exogenous wild-type p53 at 32 degrees C resulted in a rapid reduction of the number of viable cells while the parental and neo control cells remained unaffected. Cell death was due to apoptosis as shown by chromatin and nuclear condensation and specific DNA fragmentation. The first signs of apoptosis were evident after 10 h at 32 degrees C and after 3 days 90-100% of the cells had undergone apoptosis. These findings indicate an incompatibility between expression of wild-type p53 and progressive growth of BL cells if their neoplastic development has included a p53 mutation. The question whether apoptosis was induced in by the wild-type protein per se or by the contradictory signals of a constitutively activated c-myc and wild-type p53 needs further investigation.
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PMID:Wild-type p53 induces apoptosis in a Burkitt lymphoma (BL) line that carries mutant p53. 850 75

A substantial proportion of patients with primary immunodeficiency diseases develop tumors, particularly those of lymphoreticular system caused by Epstein-Barr virus (EBV). Primary immunodeficiency renders patients susceptible to EBV by reducing immune reactions and surveillance abilities against the virus or inducing overreaction of the responding cells to the antigens. Recent progress in molecular biology has unraveled the genes responsible for several types of primary immunodeficiency diseases. The cloning of the ATM gene demonstrated that the mutations in this gene were observed in the members of all the families affected with ataxia telangiectasia (AT), indicating the crucial role of this gene in the pathogenesis of AT. The protein encoded by the ATM gene shows a high sequence homology with several proteins which are presumed to be involved in the regulation of the cell cycle transition. Accumulating evidence indicates that AT-derived cells are sensitive to irradiation due to the abnormalities in p53-dependent cell cycle arrest at G1 phase. Thus, the ATM product may regulate the cell cycle at G1 phase in a p53-dependent manner and the defect of the gene may lead to the accumulation of cells with DNA damages, thereby causing malignant transformation.
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PMID:[Primary immunodeficiency diseases]. 853 51

Ninety-five cases of adenocarcinoma of the stomach were evaluated for the presence of Epstein-Barr virus (EBV) using a sensitive in situ hybridization assay targeting Epstein-Barr virus-encoded RNA 1 (EBER1) transcripts. EBER1 was detected in 11 of 95 (12%) of cases. When present, the virus was localized to malignant epithelial cells and to dysplastic gastric epithelium, but was not seen in normal-appearing gastric epithelium or intestinal metaplasia. The EBV DNA was monoclonal in all three cases tested by Southern blot analysis of the EBV terminal repeat fragment. These findings suggest that the virus was present before malignant transformation. The presence of EBV was strongly associated with increased numbers of tumor-infiltrating T lymphocytes; however, EBV was not associated with prolonged survival. Neither p53 nor bcl-2 were consistently detected in the EBV-associated tumors. Specifically, 6 of 11 EBV-positive carcinomas had accumulation of p53 protein by immunohistochemical analysis, which was similar to the prevalence of p53 accumulation in EBV-negative specimens and suggests that EBV infection does not substitute for p53 mutations during tumorigenesis. The bcl-2 oncoprotein was expressed in a third of the carcinoma specimens tested, but bcl-2 expression did not correlate with the presence of EBV or with expression of EBV latent membrane protein 1. In conclusion, EBV infection appears to precede malignant transformation in a significant fraction of gastric carcinomas, but neither bcl-2 expression nor p53 accumulation appear to be consistently associated with the presence of the virus.
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PMID:Epstein-Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. 854 6

Hypersensitivity to cross-linking agents such as mitomycin C (MMC) is characteristic of cells from patients suffering from the inherited bone marrow failure syndrome. Fanconi anemia (FA). Here, we link MMC hypersensitivity of Epstein-Barr virus (EBV)-immortalized FA lymphoblasts to a high susceptibility for apoptosis and p53 activation. In MMC-treated FA cells belonging to complementation group C (FA-C), apoptosis followed cell cycle arrest in the G2 phase. In stably transfected FA-C cells, plasmid-driven expression of the wild-type cytoplasmic FAC protein relieved MMC-dependent G2 arrest and suppressed p53 activation. However, in both FA and non-FA lymphoblasts, p53 seemed not to be instrumental in the induction of MMC-dependent apoptosis, since overexpression of a dominant-negative p53 mutant failed to affect cell survival. In addition, no differences in the level of Bcl-2 expression, an inhibitor of apoptosis, were detected between FA and non-FA cells either in the absence or presence of MMC. Our findings suggest that FAC and the other putative FA gene products may function in a yet to be identified p53-independent apoptosis pathway.
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PMID:Fanconi anemia genes act to suppress a cross-linker-inducible p53-independent apoptosis pathway in lymphoblastoid cell lines. 856 65

We analysed antibodies to Epstein-Barr virus nuclear antigens (EBNAs 1, 2, 5 and 6) and the presence of serum p53 in 100 individuals, 37 of whom has developed a haemopoietic malignancy during a 12-year follow-up of 39,000 Finnish adults. Serum p53 was detectable in six of the 63 (10%) matched controls and in 13/31 (42%) patients who developed a malignancy of lymphoid origin approximately 7 years after serum withdrawal. Six patients who developed a malignancy of myeloid origin were negative for p53. The presence of p53 alone was associated with a highly significant increased risk of lymphoid malignancies (relative risk (RR)p53 = 6.7, 95% confidence limits (CL) 1.9, 24) whereas high levels of antibody to EBNA2 seemed to be inversely related to the risk (RREBNA2 = 0.1, CL 0.0, 1.1). Among lymphoid malignancies, a combination of serum p53 and high EBNA1 antibody levels gave a greater than expected risk (RRp53 and EBNA1 = 14, CL 1.4, 130; RRexpected = 4.4), whereas interaction with high levels of EBNA5 antibody gave an expected risk (RRp53 and EBNA5 = 19, CL 1.7, 220; RRexpected = 17). Thus detectable levels of p53 appear early in the development of lymphoid malignancies, and high EBNA1 antibody levels, and accumulated p53 may both be synergistic risk indicators for lymphoid malignancies, whereas high EBNA5 antibody levels and accumulation of p53 seem to raise the RR independently of each other.
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PMID:Serum p53 accumulation and altered antibody responses to Epstein-Barr virus proteins precede diagnosis of haemopoietic malignancies of lymphoid origin. 861 41

Werner's syndrome (WS) is a human segmental progerioid disorder with an autosomal recessive pattern of inheritance. Patients with WS exhibit a number of symptoms resembling a premature aging phenotype. We have examined the fine structure of the DNA repair of UV-induced cyclobutane pyrimidine dimers in Epstein-Barr virus (EBV)-transformed WS lymphoblastoid cell lines and in a primary WS fibroblast cell line. The repair was measured at the level of the gene and also in the general genome. Gene-specific and strand-specific DNA repair was measured in the actively transcribed genes dihydrofolate reductase (DHFR), c-myc, and p53, and in the transcriptionally inactive regions, delta globin and the X-linked 754 domain. Both gene-specific repair and strand-specific repair were deficient in the transformed WS lymphoblastoid cell lines compared to normal controls. In normal cells, repair in the transcribed strand was 25 (4 h), 43 (8 h), and 72% (24 h); in the WS cells on average, repair in the transcribed strand was 18 (4 h), 27 (8 h), and 44% (24 h). However, in the primary WS fibroblast cell line, we found a pattern of preferential gene repair which was similar to that in normal human cells. In contrast to cells from patients with the gene-specific repair deficient disease Cockayne's syndrome, which show greatly delayed RNA synthesis recovery after UV irradiation, the WS cells had normal recovery of RNA synthesis. The DNA repair results differ for the different cell types, and our findings thus do not establish a general DNA repair phenotype for WS cells. The fibroblasts had proficient repair, but in the WS lymphoblasts we find a deficiency in DNA repair which could contribute to the reported hypermutability in these cells. The lymphoblasts are, however, transformed cells, and it raises the concern that biological findings in transformed cells may not reflect the situation in primary cells.
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PMID:DNA repair fine structure in Werner's syndrome cell lines. 861 4


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