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

Two Epstein-Barr virus (EBV)-associated malignancies, nasopharyngeal carcinoma and posttransplant lymphoma, rarely have mutations in the p53 tumor suppressor gene, suggesting that a viral protein interferes with p53 function. The EBV oncogene, LMP1, induces expression of the cellular antiapoptotic genes bcl-2 and A20 and could in this way interfere with p53-mediated apoptosis. Two derivatives of the p53-null epithelial cell line H1299 were prepared, one of which (H1299-p53) stably expressed a temperature-sensitive (ts) p53 protein, and another (H1299-p53+LMP1) which stably expressed both ts-p53 and latent membrane protein 1 (LMP1). At the permissive temperature, the p53 protein in the H1299-p53 cell line transcriptionally activated two of its target genes, the cyclin-dependent kinase inhibitor p21 and the mdm2 gene product, in an LMP1-independent manner. Upon serum withdrawal at the permissive temperature, p53-mediated apoptosis was induced in 50 to 60% of the cells. In the H1299-p53 cell line which stably expressed LMP1, however, only 20 to 25% of the cells underwent apoptosis. While stable expression of LMP1 did not affect levels of bcl-2 family members in these cells, it did induce expression of A20. Stable expression of A20 in the H1299-p53 cell line inhibited p53-mediated apoptosis equivalent to inhibition by LMP1. The induction of A20 may underlie the ability of LMP1 to protect EBV-infected epithelial cells from p53-mediated apoptosis.
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PMID:Epstein-Barr virus latent membrane protein 1 blocks p53-mediated apoptosis through the induction of the A20 gene. 897 Sep 91

We have previously reported that EBNA-5, one of the Epstein-Barr virus-encoded proteins, accumulates in the nuclear bodies containing PML, the promyelocytic leukemia associated protein. In this study, we examine the intranuclear distribution of SV40 large T-antigen (SV40T), the p53 tumor suppressor protein (p53), and PML in a conditionally immortalized cell line, IDH4. In IDH4 cells, the expression of SV40T is regulated by a dexamethasone (Dex)-driven promoter. Withdrawal of Dex results in down-regulation of SV40T and growth arrest, whereas addition of Dex to the growth-arrested cells results in up-regulation of SV40T and proliferation. In proliferating IDH4 cells, SV40T is concentrated in nuclear dots that are also positive for p53. Many of these dots are juxtaposed to PML positive structures but do not colocalize with them. After removal of Dex, SV40T-p53 dots gradually disappear, while the PML structures remain. Induction of SV40T in nonproliferating IDH4 cells causes a coordinated redistribution of SV40T and p53. The immunostaining for SV40T and p53 is first weak, then strong with a homogeneous distribution, and 3-4 days later becomes dot-like again. This reappearance of SV40T-p53 dots coincides with the recovery of proliferation in restimulated IDH4 cells. Also, the p53 pattern correlates with the SV40T pattern with regard to both morphology and intensity during both suppression and induction of SV40T. Taken together, our data suggest that (i) the level of p53 is coregulated with the level of SV40T in a dose-dependent fashion; (ii) the formation of SV40T-p53 nuclear dots correlates with the transformed phenotype; (iii) the SV40T-p53 dots localize preferentially to the neighborhood of PML bodies which are already present in normal cells.
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PMID:Intranuclear redistribution of SV40T, p53, and PML in a conditionally SV40T-immortalized cell line. 898 12

In 1987, we reported three patients with pleural lymphoma developed after a 22-30 year history of pyothorax resulting from artificial pneumothorax for the treatment of pulmonary tuberculosis or tuberculous pleuritis. Based on the pathologic and epidemiologic studies, we regarded the chronic pyothorax (CP) to be etiologically important in the development of pleural lymphoma. Through a nation-wide study in Japan, 37 cases of pleural lymphoma were collected. Pleural lymphoma had developed during the 20 year history of CP in all patients. Histologically all were non-Hodgkin's lymphoma with the diffuse large cell type being the most common. Immunologic and immunohistochemical studies revealed that 32 out of 33 cases were of B-cell lymphoma. From these findings, we proposed the term pyothorax-associated lymphoma (PAL). We examined the presence of Epstein-Barr virus (EBV) genome on the paraffin-embedded specimens in 34 PAL cases and 16 cases of CP alone. Combined polymerase chain reaction (PCR), in situ hybridization, and immunohistochemistry revealed that the EBV genome was detected in lymphoma cells in all PAL, but only one of the cases with CP alone. These findings suggested the etiological role of EBV for the development of PAL. We also described here the character of cell lines established from PAL, association of PAL with Kaposi's sarcoma-associated herpes virus, results of a case-control study on risk factors for development of PAL, and p53 mutations.
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PMID:Pyothorax-associated lymphoma. 899 Jun 21

Fifty-one cases of acquired immunodeficiency syndrome (AIDS)-related primary brain lymphomas (AR-PBL) were investigated for clinical characteristics; human immunodeficiency virus (HIV)-associated disorders; histopathologic features; immunophenotype; Epstein-Barr virus (EBV) infection; and, when frozen tissue was available, oncogene rearrangements. AR-PBL occurred late in the course of AIDS and were usually associated with other systemic or cerebral disorders and with a low level of CD4 lymphocytes. All cases were high grade lymphomas according to the Working Formulation or updated Kiel classification, and often displayed a multifocal pattern. Thirty cases were classified as immunoblastic with plasmacytic differentiation, 18 cases were large cell lymphomas with an immunoblastic component or centroblastic polymorphic lymphomas, and 2 were small noncleaved non-Burkitt lymphomas (Working Formulation). This latter category is classified as Burkitt's-like lymphoma in the REAL nomenclature. One case could not be classified because of necrosis. AR-PBL showed a high level expression of activation and adhesion molecules. The presence of EBV was detected in most cases, and, when PCR was used, this was a constant finding. bcl-2 oncoprotein and latent membrane protein-1 (LMP-1) were strongly expressed. None of the tested cases expressed p53, or were rearranged for bcl-2 or c-myc oncogenes. This study confirms the immunophenotypic specificity of AR-PBL, which may reflect the special immune status of the brain.
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PMID:AIDS-related primary brain lymphomas: histopathologic and immunohistochemical study of 51 cases. The French Study Group for HIV-Associated Tumors. 904 3

Posttransplantation lymphoproliferative disorders (PT-LPDs) represent a heterogeneous group of Epstein-Barr virus (EBV) associated lymphoid proliferations occurring in the setting of immunosuppression associated with solid organ transplantation. Some PT-LPDs regress after a reduction in immunosuppression, whereas others progress despite aggressive therapy. Previously defined histopathologic categories do not correlate with clonality, and neither histopathology nor clonality has reliably predicted their clinical behavior. Recently, correlative clinical, morphological, and molecular genetic analysis has suggested that PT-LPDs are divisible into three distinct clinically relevant categories as follows: (1) plasmacytic hyperplasia: most commonly arise in the oropharynx or lymph nodes, are nearly always polyclonal, usually contain multiple EBV infectious events or only a minor cell population infected by a single form of EBV, and lack oncogene or tumor suppressor gene alterations; (2) polymorphic lymphoproliferative disorders: may arise in lymph nodes or extranodal sites including the gastrointestinal tract and lungs, are nearly always monoclonal based on the presence of clonal immunoglobulin gene rearrangements, usually contain a single form of EBV, and lack oncogene or tumor suppressor gene alterations; and (3) malignant lymphoma or multiple myeloma: present with widely disseminated disease frequently including the bone marrow, are monoclonal based on clonal immunoglobulin gene rearrangements, contain a single form of EBV, and contain alterations of one or more oncogenes or tumor suppressor genes (c-myc, ras, p53). Thus, proto-oncogene and tumor suppressor gene alterations appear to be associated with disease progression and an often fatal clinical outcome. Furthermore, multiple PT-LPD lesions occurring in the same individual but in multiple anatomic sites, either simultaneously or dysynchronously over time, may show distinct clonal immunoglobulin gene rearrangement patterns and evidence of infection by different forms of EBV, suggesting that each lesion represents a distinct clonal neoplasm that may show distinctive clinical behavior. Therefore, whenever possible, a biopsy of each one of the several PT-LPD lesions occurring in an individual should be obtained to derive a true assessment of the pathobiological nature and clinical aggressiveness of an individual's disease.
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PMID:Molecular pathology of posttransplantation lymphoproliferative disorders. 904 6

The incidence of non-Hodgkin's lymphoma is greatly increased in human immunodeficiency virus (HIV)-infected individuals. Most are clinically aggressive B-cell lymphomas exhibiting Burkitt-type, immunoblastic or large-cell morphology. Approximately 80% arise systemically (nodal or extranodal), and the remaining 20% arise in the central nervous system. A small proportion are body cavity-based (primary effusion) lymphomas associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Possible factors contributing to lymphoma development include HIV-induced immunosuppression, chronic antigenic stimulation, and cytokine overproduction. These phenomena are associated with the development of oligoclonal B-cell expansions. The appearance of malignant lymphoma is characterized by the presence of a monoclonal B-cell population displaying a variety of genetic lesions including Epstein-Barr virus (EBV) infections, c-myc gene rearrangement, bcl-6 gene rearrangement, ras gene mutations, and p53 gene mutations/deletions. The number and type of genetic lesions varies according to anatomic site of origin and histopathology. In the case of Burkitt-type lymphoma, virtually 100% exhibit c-myc gene rearrangement, two thirds display p53 gene mutations, one third contain EBV, and none exhibit bcl-6 gene rearrangements. In contrast, in the case of immunoblastic lymphoma, virtually 100% contain EBV, 25% display c-myc gene rearrangements, 20% display bcl-6 gene rearrangements, and few exhibit p53 gene mutations. These findings suggest that more than one pathogenetic mechanism is operational in the development and progression of acquired immunodeficiency syndrome (AIDS)-related lymphoma. Further work is necessary to develop a thorough understanding of the origin and pathogenesis of malignant lymphoma in the setting of HIV infection. AIDS-related lymphoma remains an important biologic model for investigating the development and progression of high-grade non-Hodgkin lymphomas as well as malignant lymphomas that develop in immune-deficient hosts.
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PMID:Molecular pathology of acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. 904 11

Overexpression of the tumour suppressor gene product p53 is common in oesophageal adenocarcinoma. This may be due to gene mutation, but overexpression can also result from complexing between viral proteins and p53; a number of viruses are causally linked with malignancy. This study therefore investigated the prevalence in oesophageal adenocarcinoma of viruses whose gene products are capable of interacting with p53. Seventeen tumours and 17 normal oesophagi were screened for specific DNA sequences from human papilloma virus (HPV), Adenovirus type 12, Epstein-Barr Virus (EBV), and cytomegalovirus (CMV). Frozen sections were analysed by polymerase chain reaction, and results were confirmed by Southern blot hybridization. Overexpression of p53 was studied immunohistochemically. Overexpression of p53 was identified in 11 of 17 tumours. No viral sequences were detected for HPV, CMV, or Adenovirus in any tumour. EBV sequences were found in eight of 17 tumours, and eight of 17 negative controls. There is therefore no evidence of HPV 16, 18 and 33, Adenovirus 12 or CMV infection in oesophageal adenocarcinoma. EBV infection in the oesophagus is of doubtful significance, in view of the high incidence in the control population. Overexpression of p53 cannot be explained by complexing with common viral proteins, and must be related to other intracellular mechanisms.
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PMID:Investigation of oesophageal adenocarcinoma for viral genomic sequences. 906 43

Posttransplantation lymphoproliferative disorders (PT-LPDs) occurring in T-cell depleted (TCD) allogeneic bone marrow transplant recipients seem to be different from those that arise in solid organ recipients in their early development, the high incidence of extensive dissemination at presentation, and their aggressive course and high fatality rate. We report a series of 10 patients with PT-LPDs after TCD allogeneic bone marrow transplant. We studied the correlation between the morphology of the lesions; their clonality based on immunoglobulin (Ig) heavy chain gene rearrangement analysis and immunohistochemistry; their proliferative activity as measured by immunoperoxidase staining for the proliferating cell nuclear antigen (PCNA) and the presence of p53 gene product overexpression. Histologically, our cases corresponded to the two morphologic categories of polymorphic B-cell lymphoma (PBCL, seven cases) and malignant lymphoma immunoblastic (ML-IB, three cases). Ig light-chain staining showed monoclonality in a minority of the cases, whereas Ig gene rearrangement analysis by polymerase chain reaction revealed B-cell clonality in three of seven cases of PBCL and in all three cases of ML-IB. The Epstein-Barr virus (EBV) genome, the expression of EBV latent membrane protein or both were found in all 10 specimens. High proliferative activity (PCNA > or = 66%) was found in all cases, with a mean PCNA value of 56% in PBCL and 84% in ML-IB. Five specimens were p53+ (two of seven PBCL and three of three ML-IB). Two of four PBCL cases resolved with the administration of donor leukocytes. All of the remaining patients died of the PT-LPD within a short time from admission. Our results show that the PT-LPDs after TCD bone marrow transplantation are characterized by a high frequency of high-grade histologic subtypes, frequent monoclonality, high proliferative activity, frequent overexpression of p53 gene product, and poor prognosis. These characteristics observed in only a minority of cases of PT-LPDs occurring after solid organ transplantation may account for the less aggressive clinical behavior observed in those diseases.
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PMID:Posttransplantation lymphoproliferative disorders in bone marrow transplant recipients are aggressive diseases with a high incidence of adverse histologic and immunobiologic features. 912 10

Clinicopathological evidence has accumulated that colorectal adenocarcinoma with minimal or no glandular differentiation constitutes two entities with different prognosis. In a series of 20 predominantly nonglandular, poorly differentiated adenocarcinomas, histological features, DNA content, p53 protein expression, Ki-ras mutation, and microsatellite instability were analyzed and correlated to the biology of the tumors. In addition, the presence of Epstein-Barr virus (EBV) transcripts was tested by RNA in situ hybridization and EBV DNA was demonstrated by nested polymerase chain reaction. Histologically, 13 tumors showed small uniform cells and 7 tumors showed large pleomorphic cells. Tumors with uniform cells exhibited more commonly an expansive growth pattern (69.2% versus 0%; P < 0.025) and a dense peritumor lymphoid infiltrate (84.6% versus 14.3%; P < 0.01) resembling their gastric counterpart, solid or medullary carcinoma. These tumors showed less frequent lymph node as well as hematogeneous metastases than pleomorphic carcinomas. In addition, they were usually diploid (84.6% versus 28.6%; P < 0.05) and lacked stabilization of the p53 protein (0% versus 42.9%; P < 0.05). No significant difference between the medullary and the pleomorphic tumor type was found with respect to bcl2 expression and the occurrence of Ki-ras mutations at codon 12. In contrast, microsatellite instability was almost totally restricted to poorly differentiated adenocarcinomas of the medullary type (100% versus 14.3%; P < 0.001). Finally, polymerase chain reaction revealed EBV DNA in 5 tumor specimens, which was, however, restricted to the peritumor lymphoid infiltrate as shown by in situ hybridization. Correlation with the biology of the tumors revealed that only one patient with the uniform cell type died due to metastastic disease during the follow-up period (median, 31 months), which was the case in five of the seven patients with the pleomorphic-type carcinoma (P < 0.025). Our results clearly indicate that the poorly differentiated colonic carcinoma with minimal or no glandular structures constitute two different entities, a medullary and a pleomorphic variant, which markedly differ in their phenotype, genotype, and prognosis.
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PMID:Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics. 913 4

Epstein-Barr virus (EBV) infection was studied in a total of 412 patients with poorly differentiated gastric adenocarcinoma by in situ hybridization for EBV-encoded small RNA. EBV-specific RNA was detected in tumor cell nuclei of 83 (20.1%) of 412 gastric carcinomas, of which 60 were histologically subclassified as gastric carcinoma with lymphoid stroma (GCLS). All EBV-positive gastric carcinomas as well as 90 randomly selected EBV-negative gastric carcinomas were further studied for p53 protein expression by immunohistochemistry. The overexpression of p53 protein was demonstrated in only 7 (8.4%) of 83 EBV-positive gastric carcinomas. This was in marked contrast to the frequency of 34.4% in EBV-negative gastric carcinomas. In addition, a few p53-positive nuclei were characteristically scattered in the tumors of many EBV-positive GCLS, but this was not regarded as p53 overexpression arising from mutation of the gene. Our findings suggested that EBV-associated gastric carcinomas may arise through a different mechanism from other types of gastric carcinomas without EBV infection.
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PMID:Infrequent overexpression of p53 protein in Epstein-Barr virus-associated gastric carcinomas. 914 Jan 10


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