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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant lymphomas frequently develop in the pleural cavity of patients with long-standing pyothorax. Thus, the term pyothorax-associated lymphoma (PAL) has been proposed for this type of tumor. Most PAL are of the type diffuse lymphoma of B cell and contain Epstein-Barr virus (EBV) DNA. This article reviews the mechanism for the development of PAL. The possible contribution of EBV infection, inflammatory cytokines and other genetic lesions, including the p53 gene, towards the growth advantage of neoplastic cells is described. Although the presence of EBV is focused in PAL cells, the contribution of EBV-mediated growth promotion in PAL is limited. Another important characteristic of PAL is that the virus antigen-positive lymphoma develops in patients with pyothorax, in whom the systemic immunodeficiency is unlikely to be present. Therefore, in the course of the development of PAL, the mechanism for the evading host immune surveillance must be obvious. In this context, the production of an immunosuppressive cytokine from PAL cells, human histocompatibility leukocyte antigen class I alleles of patients with PAL, and the mutations of cytotoxic T lymphocyte epitopes in an EBV-latent antigen are described. These mechanisms could be involved in the development of PAL, an EBV-positive lymphoma developing in an immunocompetent host, and also shed light on the tumorigenesis of other EBV-positive neoplasms and on the lymphomagenesis of other inflammatory lesions.
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PMID:Mechanism for the development of pyothorax-associated lymphoma. 977 4

We attempted to infect primary gastric epithelia (PGE) with recombinant Epstein-Barr virus (EBV) carrying a selectable marker that made it possible to select EBV-infected cells. Cells dually positive for EBV-determined nuclear antigen (EBNA) and cytokeratin were detected in 3 of 21 primary cultures after 3 days of EBV inoculation. From one culture, EBV-infected cell clones were repeatedly obtained at a frequency of 3 to 5 cell clones per 10(6) cells. EBV-infected clones had enhanced population doubling and grew to attain a highly increased saturation density, together with acquisition of marked anchorage independence. The infected clones retained the ultrastructural morphology characteristic of gastric mucosal epithelium and have been growing stably for more than 18 months (corresponding to at least 300 generations) so far, in clear contrast to the parental PGE cells, which ceased growth after 60 generations. The p53 gene of the parental PGE cells was found to be overexpressed, perhaps thereby conferring the basal potential for long-term survival in vitro. Moreover, EBV infection accelerated, to a significant extent, the growth rate and agar clonability of NU-GC-3 cells, an established EBV-negative but EBV-susceptible human gastric carcinoma cell line. Both EBV-converted PGE and NU-GC-3 clones, like EBV-positive gastric carcinoma biopsy specimens, expressed a restricted set of EBV latent infection genes characterized by the absence of EBNA2 and latent membrane protein 1 (LMP1) expression. These results indicate that EBV infection causes a transformed phenotype on PGE in the setting of possible unregulated cell cycling and renders even established gastric carcinoma cells more malignant via a limited spectrum of viral latent-gene expression. This study may reflect an in vivo scenario illustrating multiphasic involvement of EBV in carcinogenesis of gastric or other epithelial cancers.
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PMID:Epstein-Barr virus promotes epithelial cell growth in the absence of EBNA2 and LMP1 expression. 988 33

Infection of human B lymphocytes with Epstein-Barr virus (EBV) in vitro induces a G0 to G1 transition followed by DNA synthesis and cell division. The virus activation of the cell cycle closely mimics the antigen-dependent normal B cell activation pathway. Infected B cells undergo blast transformation followed by the emergence of immortalized lymphoblastoid cell lines. Numerous cellular proteins are switched on in the infected cells, including p53. In view of the frequent association of wild-type p53 (wtp53) expression with growth arrest and apoptosis, p53 expression, cell viability (absence of apoptosis) and cell cycle progression at the single cell level during the first week after EBV infection were assessed. The rate of EBV infection was scored by EBNA-5 staining between 20 and 72 h after infection and varied between 20 and 25% of the cell population. All EBNA-5-positive blasts were p53-positive as well. Double staining for p53 and for DNA ends (TUNEL) revealed that p53-positivity and apoptosis were mutually exclusive. Quantification of the DNA content by Hoechst staining and computer-assisted image analysis showed that a fraction of the p53-positive blasts had a DNA content higher than 2N, indicating entry into the S/G2 phases. Double p53 and BrdU staining of the cells, pulse-labelled with BrdU, revealed that 65% of the p53-positive blasts were in S phase 3 days after infection. Similarly, B cell activation by CD40L and IL-4 induced p53 expression without any adverse effect on cell cycle progression. Therefore, the phenomenon is not EBV-specific but correlates with immunoblast activation.
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PMID:Epstein-Barr virus infection and mitogen stimulation of normal B cells induces wild-type p53 without subsequent growth arrest or apoptosis. 1021 69

Primary mediastinal B-cell lymphoma (PMBL) shows chromosome 9p anomalies in 50% of cases. Based on reports that p16INK4A gene, located on this chromosomal arm, is frequently altered in aggressive lymphomas, we analysed for alterations of this gene in 27 cases of PMBL, which were part of a series of 32 PMBL cases that have been characterized for alterations in c-myc, p53, N-ras, bcl-1, bcl-2, bcl-6 and for Epstein-Barr virus (EBV) infection. Four cases showed p16INK4A gene anomalies, including three with promoter methylation and one homozygous deletion. Eight PMBLs showed c-myc rearrangements. Three additional cases showed sequence variations in the c-myc P2 promoter, two of which consisted of the same germline variation involving a novel polymorphic XhoI site. Four tumours contained p53 gene mutations and three had clonal EBV infection. One case had a bcl-6 rearrangement. In conclusion, our study shows that p16INK4, c-myc and p53 alterations occur in 15%, 25% and 13% of PMBLs, respectively. EBV monoclonality was found in 9% of cases, whereas no abnormality was detected in bcl-1, bcl-2 and N-ras. Thus, none of the common genetic aberrations seen in other types of non-Hodgkin's lymphomas appears to be stringently involved in the pathogenesis of this unique lymphoma type.
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PMID:Molecular features of primary mediastinal B-cell lymphoma: involvement of p16INK4A, p53 and c-myc. 1052 30

Sinonasal undifferentiated carcinoma, olfactory neuroblastoma and malignant melanoma of the sinonasal regions are included within the category of small round cell tumors of the sinonasal region. It is difficult to diagnose these tumors on the basis of light-microscopic features alone, but, in some instances, immunohistochemical staining evaluating cytokeratin and S-100 protein, for example, is of value. On the other hand, the sinonasal region is a significant site for Epstein-Barr-virus (EBV)-related tumors, including sinonasal undifferentiated carcinoma or malignant lymphoma. Twenty-three sinonasal small round cell tumors (SSRCT) comprising 5 sinonasal undifferentiated carcinomas, 9 olfactory neuroblastomas and 9 malignant melanomas were evaluated for the presence of EBV infection by in situ hybridization for EBV-encoded RNA, combined with immunostaining for EBV-related proteins (LMP-1 and EBNA2). Furthermore, 55 SSRCT comprising 37 sinonasal undifferentiated carcinomas, 9 olfactory neuroblastomas, and 9 malignant melanomas were examined for the presence of cytokeratins (AE1/ AE3 and CAM5.2), S-100 protein and p53 protein using immunohistochemical staining. According to in situ hybridization for detecting EBV-encoded RNA 1 (EBER1), all of the sinonasal undifferentiated carcinomas showed clear, intense hybridization signals localized over the nuclei of the tumor cells and, in 3 out of 9 (33.3%) malignant melanomas, hybridization signals were also recognized. However, none of the olfactory neuroblastomas revealed hybridization signals. Immunohistochemically, 4 out of 5 (80%) sinonasal undifferentiated carcinomas were positive for LMP-1, whereas only 2 out 9 (22.2%) malignant melanomas and no olfactory neuroblastomas were positive. With regard to EBNA2, sinonasal undifferentiated carcinomas, malignant melanomas and olfactory neuroblastomas were all negative. Out of 37 sinonasal undifferentiated carcinomas 35 (94.6%) showed a diffuse positive immunoreaction for AE1/AE3, whereas neither olfactory neuroblastoma nor malignant melanoma revealed a positive reaction. All 9 malignant melanomas and 6 out of 9 olfactory neuroblastomas (75%) were positive for S-100 protein, whereas only 6 cases of sinonasal undifferentiated carcinomas (19.4%) were positive. As for p53 protein, 16 of 37 sinonasal undifferentiated carcinomas (43.2%) were positive, whereas neither olfactory neuroblastoma nor malignant melanoma revealed any positive reaction. The above results suggest that EBV infection is closely associated with sinonasal undifferentiated carcinomas, and that some malignant melanomas may also have a relationship with its infection. For the differential diagnosis of SSRCT, it is important to evaluate EBV infection along with immunohistochemical staining for cytokeratins and S-100 protein. The overexpression of p53 protein was found to be related to the oncogenesis of sinonasal undifferentiated carcinoma; however, there was no association between its overexpression and malignant melanoma or olfactory neuroblastoma.
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PMID:Evaluation of Epstein-Barr virus infection in sinonasal small round cell tumors. 1064 44

Cell cycle dysregulation as measured by p53 protein expression and latent Epstein-Barr (EBV) infection are important in the pathogenesis of lymphoma, particularly in immunosuppressed patients. Although latent EBV commonly is detected in lymphomas arising in patients with connective tissue disease who are immunosuppressed with methotrexate, p53 protein expression has not been reported. We compared the immunohistologic expression of p53 protein and the incidence of latent EBV infection in lymphomas arising in patients with connective tissue disease treated and not treated with methotrexate. Increased p53 staining was detected in 10 of 11 lymphomas arising in patients after methotrexate therapy vs 5 of 11 in patients not treated with methotrexate. Latent EBV was detected in 7 of 13 lymphomas arising in patients after methotrexate therapy vs 2 of 11 in patients not treated with methotrexate. Concordant p53 expression and latent EBV were detected in 5 of 7 lymphomas arising after treatment with methotrexate, including 1 that regressed after methotrexate therapy was withdrawn. These findings suggest that cell cycle dysregulation and EBV-related transformation are important in the pathogenesis of lymphomas arising in patients with connective tissue disease who are immunosuppressed with methotrexate.
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PMID:Lymphomas in patients with connective tissue disease. Comparison of p53 protein expression and latent EBV infection in patients immunosuppressed and not immunosuppressed with methotrexate. 1066 23

Clinicopathological analysis, microsatellite analysis, detection of Epstein-Barr virus (EBV), and immunohistochemistry on p53 protein were performed in 26 cases of gastric remnant cancer (GRC). They were divided into two groups; Group A (n = 14) who had undergone a primary gastrectomy for benign gastric disease, and Group B (n = 12) who had undergone the same operation for gastric cancer. EBV infection was present in 29% of Group A, 8% of Group B and 6% of the conventional gastric carcinoma (CGC) (Group A vs CGC, P = 0.01). Microsatellite instability (MSI) was found in 7% of Group A, 25% of Group B, and 9% of the CGC (Group B vs CGC; P = 0.08). p53 Overexpression was observed in 46% of the GRC and 33% of the CGC. p53 Overexpression was observed in 90% of the intestinal type of GRC, but in only 20% of the diffuse type of GRC (P = 0.002). The cancer stage was a significant factor in the univariate analysis of survival (P = 0.04). In conclusion, GRC is different from CGC in terms of MSI or EBV association. The pathogenetic differences between the two groups require further investigation. EBV infection may have been involved in the carcinogenesis of Group A. MSI may be an important factor in the carcinogenesis of metachronous multiple gastric cancer (Group B).
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PMID:Microsatellite instability and Epstein-Barr virus infection in gastric remnant cancers. 1088 25

Interaction between viral proteins and tumor suppressor p53 is a common mechanism of viral pathogenesis. The Epstein-Barr virus (EBV) BZLF-1 ORF-encoded ZEBRA protein (also denoted EB1, Z, Zta) binds to p53 in vitro and has been associated with the altered transcription of p53-regulated genes in B lymphocytes and epithelial cells. In this work, Jurkat T-lymphoblastoid cells that express ZEBRA were characterized by the use of transiently transfected p53 and p53 reporter genes. Stable expression of ZEBRA was associated with the activation of p53-dependent transcription and increased p53 dependent apoptotic cell death. In Jurkat cell lines, stably expressed ZEBRA protein was apparently localized to the cell cytoplasm, in contrast to the typical nuclear localization of this protein in other cell types. Previous studies have suggested that EBV infection of T lymphocytes may contribute to the malignant transformation of T cells and the increased replication of human immunodeficiency virus. Our observations suggest a mechanism through which ZEBRA protein expressed in human T lymphocytes could alter T-cell proliferation and apoptosis during EBV infection. (Blood. 2000;96:625-634)
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PMID:Stable expression of Epstein-Barr virus BZLF-1-encoded ZEBRA protein activates p53-dependent transcription in human Jurkat T-lymphoblastoid cells. 1088 27

The experiments were designed to study correlation between frequency of apoptosis of Reed-Sternberg/Hodgkin (R-S/H) cells, EBV infection of these cells, expression of the key proteins involved in regulation of apoptosis and cell cycle in R-S/H cells, the patients' pretreatment markers and the clinical outcome. One hundred and ten Hodgkin's disease (HD) patients were studies, of which 69 obtained complete remission (CR) after first-line treatment and 41 did not respond. The time of follow-up was from 18 to 242, median 69.7, months. Apoptosis was evaluated by TUNEL technique (TdT-mediated dUTP nick end labeling) and the presence of EBV-latent membrane protein 1 as well as expression of Bcl-2, tumor suppressor p53, p21WAF1, MDM-2, Rb1, PCNA, p27KIP1 and caspase-3, was detected immunocytochemically on paraffin-embedded lymph node specimens obtained at diagnosis. Positive TUNEL reaction was found in 43 patients with apoptotic index (AI) in this group varying between 10% and 60%. In the remaining 57 patients AI of R-S/H cells was below 10%. In 62 patients the cells surrounding R-S/H cells were also TUNEL-positive; their frequency was variable. The expression of LMP1 protein on R-S/H cells was found in 38 patients, without any correlation with the presence or frequency of apoptosis. No significant difference was seen between the AI and both clinical stage and histological type of the disease. However, the mean AI in non-responding patients was significantly higher than in CR group (p=0.015); the high frequency of apoptosis was also negatively correlated with the progression free survival time (p=0.031) and the overall survival (p=0.042). The expression of PCNA, p21WAF1, p53 protein and caspase-3 also showed positive correlation with frequency of apoptosis (p=0.011, p=0.036, and p=0.001, respectively). On the other hand, no statistically confirmed correlation was found between AI and expression of bcl-2, MDM-2, Rb1, and p27KIP1 on R-S/H cells. These data provide evidence that tumor cells in HD undergo spontaneous apoptosis regardless of EBV infection. High pretreatment AI correlates with poor response to the treatment, and may be considered as a potential negative prognostic factor in HD.
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PMID:Spontaneous apoptosis of Reed-Sternberg and Hodgkin cells; clinical and pathological implications in patients with Hodgkin's disease. 1093 5

Posttransplant lymphoproliferative disorders (PTLDs), which are highly associated with Epstein-Barr virus infection, have a low frequency of molecular genetic abnormalities. Recently it has been suggested certain EBV substrains may be associated with specific lymphoma subtypes. The goals of our study were two fold: 1) to determine the prevalence of EBNA-1 substrains and prognostic utility in PTLD and 2) to determine the incidence of p53 gene mutations and p53 protein overexpression in 32 EBV-positive PTLD cases. Tumor DNA was sequenced to identify EBNA-1 substrains at codon 487 and p53 gene mutations in exons 5-8. The PTLD samples contained the following EBNA-1 substrains: P-thr in 17/32 (53%), P-ala in 11/32 (34%), and V-leu in 4/32 (13%). More heterogeneity within major subtypes was seen in the PTLD cases than in the referral group. A second group of 25 referral (non-PTLD) samples including infectious mononucleosis (6) and sequential EBV positive virology samples (19) contained P-thr in 17/25 (68%); P-ala in 2/25 (8%); and V-leu in 6/25 (24%). In the 29 B-cell PTLD the time to presentation was an average of 13.3 months in the P-ala group, 16.6 months in the P-thr group, and 40.6 months in the V-leu group: (p>0.05). There was no difference in survival in patients (median overall--60 months) between the three different substrains of EBNA-1 (Log rank test, p=0.39). One of 31 (4.1%) cases (a diffuse large cell B-cell) had a p53 mutation. Seven of 31 (23%) cases (all B-cell), including the p53 mutated case, had over-expression of p53 protein. We conclude EBNA-1 substrains vary in PTLD and suggest the pattern reflects the geographical incidence of substrains in the region. We also conclude p53 mutations are not a significant molecular genetic abnormality in PTLD.
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PMID:Molecular epidemiology of EBNA-1 substrains of Epstein-Barr virus in posttransplant lymphoproliferative disorders which have infrequent p53 mutations. 1095 78


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