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)

The novel human pre-B cell line OZ was established from a patient with an aggressive form of non-Hodgkin's lymphoma. Karyotypic analysis of both the primary tumour and OZ cells revealed several marker chromosomes, including the t(14;18)(q32;q21) translocation, which involves the Bcl-2 gene, and alterations on chromosome 17p. Southern blot analysis found identical rearrangements in the 5' region of Bcl-2 gene in the primary tumour and OZ cells. Homozygous deletions of the p15INK4B and p16INK4A genes, however, were present only in OZ cells. Western blot analysis detected aberrant small molecular-weight p53 proteins in both cell types. In addition, OZ cells no longer expressed the CD20 antigen. These findings suggest that Bcl-2 gene rearrangement and aberrant p53 expression resulted in the original B-cell tumour. A subsequent transforming event involving the p15INK4B and p16INK4A genes may have generated more immature cells with a growth advantage during in vitro culture. The genetic alterations involving p53, p15INK4B, and p16INK4A may be implicated in the aggressive form of t(14;18)(q32;q21)-bearing tumours and their poor prognosis.
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PMID:Establishment of a novel human B-cell line (OZ) with t(14;18)(q32;q21) and aberrant p53 expression was associated with the homozygous deletions of p15INK4B and p16INK4A genes. 960 Jan 10

p27Kip1 is a cyclin-dependent kinase inhibitor that regulates the decision to enter S phase or withdraw from the cell cycle. In resting cells, the level of p27Kip1 provides an inhibitory threshold above which G1 cyclin D/E/cyclin-dependent kinases accumulate before activation; however, in cycling cells, p27Kip1 protein is sequestered by high levels of active cyclin D/cyclin-dependent kinase 4 complexes. As a group, the cyclin-dependent kinase inhibitors have been proposed to act as tumor suppressor genes, and several members have been implicated in the pathogenesis of a variety of human cancers. We examined p27Kip1 expression in 116 non-Hodgkin's lymphomas including 50 cases of MCL (40 typical and 10 blastic variants), 21 follicular lymphomas, 20 diffuse large B-cell lymphomas, 16 chronic lymphocytic leukemias, 8 marginal zone B-cell lymphomas, and 1 splenic marginal zone lymphoma, and correlated its expression with that of the proliferation marker Ki67 (MiB1) and with p53. p27Kip1 gene structure was analyzed by Southern blot in the group of MCLs. In all cases of non-Hodgkin's lymphoma other than MCL, p27Kip1 expression was inversely related to the proliferation index as measured by Ki67. In contrast, in typical MCL, p27Kip1 expression was negative in 35 of 40 (88%) cases, irrespective of the proliferative rate (median 15%; range 2 to 90%). Paradoxically, in the blastic variant of MCL, 8 of 10 (80%) cases showed expression of p27Kip1, despite a high proliferation rate (median 60%; range 32 to 100%). However, the staining in most of the cases was less intense than in the reactive T lymphocytes. Deletions of p27Kip1 gene were not found in any of the 25 cases examined. p53 expression was found in 15 of 50 cases of MCL: 7 of 10 (70%) in the blastic variant and 8 of 40 (20%) in the typical MCL (70% vs. 20%, P < 0.0045). These results demonstrate that MCLs, in contrast to other non-Hodgkin's lymphomas and normal lymphoid tissue, fail to correlate p27Kip1 expression with the proliferation rate. This peculiar uncoupling of p27Kip1 protein expression from the proliferation rate may be related to the high levels of cyclin D1 expressed in MCL and is likely to have profound effects on cell cycle regulation and contribute to the pathogenesis of MCL.
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PMID:Mantle cell lymphomas lack expression of p27Kip1, a cyclin-dependent kinase inhibitor. 966 78

Mutations of the p53 tumor suppressor gene have been used as molecular genetic markers of disease and serve as a prognostic indicator in various malignancies including non-Hodgkin's lymphoma (NHL). Alterations in the p53 gene were investigated in a bone marrow sample from a NHL patient admitted for autologous bone marrow transplantation. Diffuse mixed small and large cell NHL, was initially diagnosed which eventually progressed to large cell lymphoma at relapse following poly-chemotherapy. A sequential technique of polymerase chain reaction-mediated single-strand conformational polymorphism (PCR-SSCP) of the p53 gene revealed a shift in one band of exon 6 in the bone marrow, collected at the time of initial diagnosis. No mutations were detected in exons 5, 7, 8 and 9. Direct sequencing of exon 6 detected a single base change from G to C resulting in an amino acid substitution from glycine to histidine. Results of this study and data reviewed from other publications suggest that the missense p53 mutation seen in this patient at the time of diagnosis may perhaps have been used to predict the eventual outcome of the disease. This could, therefore, serve as an important genetic disease marker particularly in bone marrow or peripheral blood samples initially collected and cryopreserved for future possible autologous transplantation.
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PMID:p53 gene mutation in the bone-marrow of a patient with diffuse mixed cell type lymphoma at diagnosis predicting eventual progression to large cell lymphoma. 968 39

Alterations in the p53 gene are less common in hematological malignancies (10 to 15%) than in solid tumors, and usually consist in point mutations, which can be readily detected using SSCP or ICC. In most cases (except in non-Hodgkin's lymphoma) there is a close correlation between point mutations and a positive ICC. In myelodysplastic syndromes, acute myeloid leukemia, chronic myeloid leukemia, and chronic lymphoid leukemia, point mutations affecting one allele are accompanied with deletion of the other allele. The complete absence of the p53 gene in these conditions probably explains the poor prognosis and resistance to chemotherapy in these patients. In contrast, in the L3 form of acute lymphoid leukemia and Burkitt's non-Hodgkin's lymphoma, punctual mutations are common (30%) and rarely accompanied with deletion of 17p. These data confirm the key role of p53 in the induction of apoptosis after chemotherapy and support the need for developing tools for transferring the p53 gene into malignant cells with the goal of restoring chemosensitivity.
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PMID:[p53 and hematologic malignancies]. 976 55

Mitoguazone (methylglyoxal bisguanylhydrazone, methyl-GAG or MGBG) is a synthetic polycarbonyl derivative with activity in patients with Hodgkin's and non-Hodgkin's lymphoma, head and neck cancer, prostate cancer, and esophageal cancer. Mitoguazone has also recently been documented to have activity in patients with AIDS-related lymphoma. Among anticancer drugs, mitoguazone has a unique mechanism of action via interference with the polyamine biosynthetic pathway. Polyamines stabilize DNA structure by non-covalent cross-bridging between phosphate groups on opposite strands. In addition, mitoguazone causes uncoupling of oxidative phosphorylation. In this study, the ability of mitoguazone to induce apoptosis by inhibiting the polyamine pathway was assessed in three Burkitt's lymphoma cell lines (Raji, Ramos and Daudi) and one prostate carcinoma cell line (MPC 3). Additional evaluations were performed in two human breast cancer cell lines (MCF7 with wild-type p53 and VM4K with mutated p53) to determine whether the p53 tumor suppressor gene was required for efficient apoptosis induction. The present study demonstrated that mitoguazone induces apoptosis in all the different human cancer cell lines tested in a concentration- and time-dependent way, and triggers a p53-independent programmed cell death in the human breast cancer MCF7 cell line.
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PMID:Mitoguazone induces apoptosis via a p53-independent mechanism. 977 8

The PAX-5 gene codes for the transcription factor BSAP, which is expressed throughout B-cell development. Although loss-of-function mutation in the mouse showed an essential role for Pax-5 in early B lymphopoiesis, gain-of-function mutations have implicated the human PAX-5 gene in the control of late B-cell differentiation. PAX-5 (on 9p13) has been involved together with the immunoglobulin heavy-chain (IgH) gene (on 14q32) in the recurring t(9;14)(p13;q32) translocation that is characteristic of small lymphocytic lymphoma with plasmacytoid differentiation. Here we have characterized a complex t(2;9;14)(p12;p13;q32) translocation present in a closely related non-Hodgkin's lymphoma referred to as splenic marginal zone lymphoma (MZL). In this MZL-1 translocation, the two promoters of PAX-5 were replaced on the derivative chromosome 14 by an immunoglobulin switch Smicro promoter that was linked to the structural PAX-5 gene upstream of its translation initiation codon in exon 1B. Expression analyses confirmed that PAX-5 transcription was upregulated due to efficient initiation at the Smicro promoter in the malignant B lymphocytes of patient MZL-1. For comparison we have analyzed PAX-5 expression in another B-cell lymphoma, KIS-1, indicating that transcription from the distal PAX-5 promoter was increased in this tumor in agreement with the previously characterized translocation of the immunoglobulin Emicro; enhancer adjacent to PAX-5 exon 1A. In both lymphomas, the J-chain gene, which is thought to be under negative control by BSAP, was not expressed, whereas transcription of the putative target gene p53 was unaffected by PAX-5 overexpression. Together these data indicate that the t(9;14)(p13;q32) translocation contributes to lymphoma formation as a regulatory mutation that leads to increased PAX-5 expression in late B-cell differentiation due to promoter replacement or enhancer insertion.
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PMID:Deregulated PAX-5 transcription from a translocated IgH promoter in marginal zone lymphoma. 980 80

We report a case with a germline mutation of the p53 gene develpoing both a non-Hodgkin's lymphoma and an astrocytoma. The astrocytoma could be cured by two operations and combined chemotherapy but 33 months after the onset of the disease, he suffered from a diffuse, large cell centroblastic malignant lymphoma of B-cell lineage. In spite of clear rearranged fragments observed with IgH and c-MYC gene probes, we could not diagnose a Burkitt's lymphoma morphologically. The malignant lymphoma was chemoresistant and the patient died of multi-organ failure. He was confirmed to have a germline mutation of the p53 gene by analysis of c-DNA from peripheral lymphocytes and loss of heterozygosity (LOH) of p53 was evident in the lymphoma. The results were suggestive of the Li-Fraumeni syndrome (LFS), a rare autosomal dominantly inherited syndrome with a germline mutation of p53 gene and diverse malignancies, but this could not be confirmed in the present case. Alternatively, a de novo mutation could have been involved.
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PMID:Astrocytoma and B-cell lymphoma development in a man with a p53 germline mutation. 983 5

Mantle cell (centrocytic) non-Hodgkin's lymphoma (MCL) is a malignant tumour with unique biological features. The pathogenesis of MCL seems to be strongly associated with aberrant function of the cell cycle. 110 cases of MCL have been analysed for their cytomorphological features, mitotic and proliferation indices, bcl-1 rearrangements, p53 expression patterns and DNA content by both interphase cytogenetic as well as DNA flow cytometric analyses. According to cytomorphology, three subtypes were recognized: a common, a lymphoblastoid and a pleomorphic variant of MCL. Blastic MCL subtypes were characterized by distinctly elevated mitotic and proliferation indices, frequent bcl-1 rearrangements at the MTC locus, and overexpression of p53. The most interesting finding, however, was a striking tendency of blastoid MCL subtypes to harbour chromosome numbers in the tetraploid range, a feature clearly separating these neoplasms from other types of B-cell NHL and possibly being related to its unphysiological expression of cyclin D1. Although characterised by a uniform immunophenotype and common biological background, MCL shows a broad spectrum of morphological features ranging from small cell to blastic types, and this spectrum is mirrored by distinct biological features.
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PMID:The cytomorphological spectrum of mantle cell lymphoma is reflected by distinct biological features. 1003 1

There is evidence that the incidence of primary cutaneous lymphoma, like other forms of non-Hodgkin's lymphoma, is increasing, yet little is known of the pathogenetic events involved in this group of disorders. In this study we examine the frequency and spectrum of P53 gene mutations in a large series of primary cutaneous lymphomas, with particular emphasis on tumor stage mycosis fungoides, as it is in these cases that p53 overexpression has previously been reported. Sixty-six samples from 55 patients with primary cutaneous B cell and T cell lymphomas were analyzed for mutations in exons 5-9 of the P53 gene using polymerase chain reaction/single strand conformational polymorphism, and subsequent cloning and sequencing of genomic DNA. Fourteen separate P53 mutations were identified in blood, skin, and lymph node samples in 13 patients (24%). Twelve of 14 mutations occurred at dipyrimidine sites, eight resulting in C-->T transitions and one in a CC-->TT tandem base transition, a mutation spectrum strikingly similar to that reported in nonmelanoma skin cancer and characteristic of DNA damage caused by ultraviolet B radiation. In the subset of patients with mycosis fungoides, P53 mutations were identified in six of 17 patients with tumor-stage but in none of 12 patients with plaque-stage disease (Fisher's exact test p = 0.027). These data suggest a role for ultraviolet radiation in the pathogenesis of primary cutaneous lymphomas and a possible ultraviolet B-related step in the progression of mycosis fungoides from plaque to tumor-stage disease.
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PMID:Spectrum of p53 gene mutations suggests a possible role for ultraviolet radiation in the pathogenesis of advanced cutaneous lymphomas. 1008 8

A clinicopathologic study was conducted to assess the implication of HTLV-I infection, Strongyloides stercoralis (Ss) infection, and P53 overexpression in the development, response to treatment, and evolution of non-Hodgkin's lymphoma (NHL) in Martinique, French West Indies. Two groups of patients, with 22 and 41 participants with B-cell and T-cell lymphoma, respectively, were analyzed. HTLV-I antibodies were detected in 24 (59%) patients with T-cell lymphoma of whom 19 (46%) fulfilled diagnostic criteria of adult T-cell leukemia/lymphoma (ATLL). By comparison with other T-cell lymphomas, patients with ATLL were significantly younger (52 versus 63 years; p = .03), had a significantly higher incidence of hypercalcemia (60% versus 0%; p = .0001), a trend for higher incidence of digestive tract localization (21% versus 4%; p = .1) and significantly shorter median survival (6 versus 17 months; p = .03). Similar results were observed when all 24 HTLV-I-infected patients with T-cell lymphoma were compared with the 17 seronegative patients. Strongyloidiasis was diagnosed in 11 of 34 patients tested for Ss infection. All 4 Ss-infected (Ss-positive) ATLL patients treated with combination chemotherapy achieved complete remission (CR) versus only 2 of 7 Ss-negative ATLL patients (p = .04). In addition, survival of Ss-positive patients with ATLL was better than that of the uninfected patients: 27 versus 5 months, p = .04, respectively). P53 expression was assessed by immunohistochemistry on lymph node biopsies from 37 patients including 18 B-cell lymphomas, 14 ATLL, and 5 other T-cell lymphomas. P53 overexpression (P53-positive) was observed in 6 samples that corresponded in all 6 patients with ATLL. All P53-positive ATLL patients had stage IV disease with elevated lactate dehydrogenase (LDH) levels. By comparison with other ATLL patients studied for p53 expression, P53-positive ATLL were characterized by a lower response rate to combination chemotherapy (CR: 0 of 6 versus 4 of 6; p = .04) and a shorter survival (2 versus 9 months, p = .04). Our results suggest that ATLL represents almost 50% of T-cell lymphomas in Martinique; Ss infection during ATLL seems to be linked with a high response rate to chemotherapy and prolonged survival; and P53 overexpression is observed in almost 50% of aggressive ATLL from Martinique and, even in advanced clinical subtypes, is associated with resistance to chemotherapy and short-term survival.
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PMID:Implication of HTLV-I infection, strongyloidiasis, and P53 overexpression in the development, response to treatment, and evolution of non-Hodgkin's lymphomas in an endemic area (Martinique, French West Indies). 1009 85


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