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

The relationship between the expression of a transformation-related cellular-encoded phosphoprotein, p53, and the potential to form distant metastases was investigated in Abelson murine leukemia virus-transformed murine large cell lymphoma sublines of differing metastatic behaviors. Low metastasis RAW117-P and high metastasis RAW117-H10 cells were labeled with 35S-methionine, and several anti-p53 monoclonal antibodies were used to immunoprecipitate p53 from the cell lysates. Using these procedures, similar amounts of p53 were detected in the RAW117-P and -H10 cells. In addition, the expression of 2.0 Kb mRNA containing p53-specific sequences was equivalent in RAW117-P and -H10 cells. The results indicate that p53 expression, although apparently required for neoplastic transformation, is not quantitatively related to metastatic behavior in RAW117 large cell lymphoma cells.
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PMID:The expression of transformation-related protein p53 and p53-containing mRNA in murine RAW117 large cell lymphoma cells of differing metastatic potential. 639 97

Murine strains which bear constitutive inactivating mutations of either the APC or the p53 tumor suppressor genes are characterised by spontaneous tumors. APC mutated (Min) mice develop large and small bowel adenomas, a small proportion of which, in time, become malignant. p53 deficient mice develop predominantly lymphoma and sarcoma. By interbreeding these strains we have shown that there is co-operativity between these mutations, leading to a shift in phenotype. Most notably, this was characterised by a range of abnormalities of the exocrine pancreas in 83% of animals heterozygous for the APC mutation and constitutively null for functional p53. Dysplasia and preneoplastic foci were seen in 61% of these animals and pancreatic acinar cell adenocarcinoma in 22%. Analysis of these tumors showed them to have lost the remaining wild-type copy of APC. Similar loss of APC was not associated with the development of other extra-intestinal tumors. Surprisingly, given the proposed role for loss of function mutations of the p53 gene in the development of human colorectal cancer, we have found no evidence for either an increase in the rate of adenoma formation in APC +/-, p53 -/- animals, or an increased rate of progression to malignancy compared with APC +/- p53 +/+ mice. These findings highlight striking tissue-specific differences in the tumor suppressor effects of p53.
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PMID:Interaction between murine germline mutations in p53 and APC predisposes to pancreatic neoplasia but not to increased intestinal malignancy. 747 22

Mice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53-deficient mice (p53+/- and p53-/-) and their wild-type littermates (p53+/+) of two different genetic backgrounds (129/Sv and mixed C57BL/6 x 129/Sv) up to 2 yr of age. p53+/- and p53-/- 129/Sv mice show accelerated tumorigenesis rates compared with their p53-deficient counterparts of mixed C57BL/6 x 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53-/- males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 x 129/Sv mice and never in 129/Sv p53+/- males. In the study reported here, we further characterized the lymphomas that arose in the p53-nullizygous mice and found that over three-quarters of the lymphomas were of thymic origin and contained primarily immature (CD4+/CD8+) T-cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B-cell type. The high incidence of early-onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li-Fraumeni syndrome, a human inherited cancer predisposition.
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PMID:Effects of genetic background on tumorigenesis in p53-deficient mice. 754 19

Bryostatin 1 (Bryo1), a macrocyclic lactone and a protein kinase C activator, is isolated from the marine bryozoan Bugula neritina. In this study we describe its effect, alone or after sequential use with vincristine (VCR), on the human diffuse large cell lymphoma cell line WSU-DLCL2. Our results show that both Bryo1 and VCR induced apoptosis as demonstrated by morphological examination, DNA flow cytometry (FCM), and DNA fragmentation on agarose gel electrophoresis. Cells pretreated for 24 h with Bryo1 and then exposed to VCR showed an increase in apoptosis compared to cells that were exposed to Bryo1 or VCR alone. We also studied the effects of Bryo1, VCR and their combination on cell growth, bcl-2 and p53 expression, and inhibition of cell proliferation as measured by [3H]-thymidine incorporation. Cell analysis showed significant growth inhibition of WSU-DLCL2 cells by the Bryo1/VCR combination as compared to either agent alone. Immunocytochemistry (ICC) revealed that relative bcl-2 oncoprotein expression was decreased in cells treated with Bryo1, or VCR separately and was abolished by combining both drugs. When examined by ICC, WSU-DLCL2 cells were initially negative for the p53 protein. However, upon treatment with the above agents, the relative expression of p53 was moderate on Bryo1-or VCR-treated cells and strong on cells treated with the Bryo1/VCR combination. Cell proliferation as measured by [3H]-thymidine incorporation revealed significant inhibition of tumor growth by exposure to the agents when compared to the control. In contrast, Bryo1, VCR and their combination did not show any inhibition of normal bone marrow growth. These findings taken together, suggest that the exposure of WSU-DLCL2 cells to Bryo1 prior to treatment with VCR enhances apoptosis, a phenomenon which might be exploited for future therapies.
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PMID:Bryostatin 1 induces apoptosis and augments inhibitory effects of vincristine in human diffuse large cell lymphoma. 756 78

The invention of the polymerase chain reaction (PCR) has facilitated the development of a new class of assays to quantify human somatic mutations in vivo, based on genotypic selection of mutants at the DNA level rather than phenotypic selection of mutants at the cell level. Use of these assays has provided new perspectives on the timing, location and distribution of somatic mutagenesis in mitochondrial genes and in oncogenes of the aging human body. This descriptive information has led to the inference and development of new models for age-related pathophysiology and oncogenesis. Mutations of mitochondrial genes rise rapidly with age to frequencies a thousand fold higher than those of nuclear genes. Genotypic selection analysis has revealed that mitochondrial mutations accumulate predominantly in non-mitotic cells whose age-dependent loss is associated with pathology. Random mitochondrial mutation is most likely to inactive Complex I, a deficiency of which induces mitochondrial superoxide formation and cell death. Genotypic selection of oncogenic mutations at the BCL2 and p53 loci has revealed that the cell specificity of oncogenic mutations in persons without cancer correlates well with sites of tumor origin, indicating that cells bearing such mutations are the likely precursors of future tumors. Quantitative variation in human BCL2 mutation frequency is extensive, and BCL2 mutation frequency rises with age, concordant with increased risk for lymphoma. The clonality and persistence of BCL2 mutations suggests two specific testable mechanisms of lymphomagenesis. BCL2 mutation frequency rises in persons exposed to cigarette smoke, and more p53 mutations occur in skin exposed to sunlight than in unexposed skin. Thus, in addition to their likely relevance to future cancer risk, the dose-response relationship between exposure and oncogenic mutations indicates promise for their future use as in vivo biodosimeters of human exposure to carcinogens.
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PMID:Genotypic selection of mitochondrial and oncogenic mutations in human tissue suggests mechanisms of age-related pathophysiology. 756 70

We have previously shown that exogenous wild type p53 induces apoptosis in the Burkitt lymphoma line BL41 that carries endogenous mutant p53, using a temperature sensitive p53 construct expressed as mutant p53 at 37 degrees C and wild type p53 at 32 degrees C (Ramqvist et al., Oncogene, 8, 1495-1500, 1993). We also found that wild type p53-induced apoptosis is blocked by bcl-2 in a mouse T lymphoma line (Wang et al., Oncogene, 8, 3427-3431, 1993) The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) can protect Burkitt lymphoma cells from apoptosis induced by low serum. In order to test if LMP1 can block p53-triggered apoptosis, we infected BL41 cells expressing the ts p53 construct with an LMP1-carrying retrovirus. The LMP1-expressing BL41-ts p53 cells were arrested in G1 upon induction of wild type p53 expression at 32 degrees C, but did not enter apoptosis as shown by the absence of positive TUNEL staining. WAF1/p21 mRNA was induced at 32 degrees C in both the ts p53-expressing and ts p53/LMP1-expressing BL41 cells. Thus, LMP1 prevents p53-induced apoptosis but does not interfere with induction of WAF1/p21. The LMP1-infected cells expressed elevated bcl-2 protein levels. Therefore, our data suggest that LMP1 blocks p53-triggered apoptosis but not G1 arrest by upregulating bcl-2 expression.
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PMID:The EBV-encoded LMP1 protein inhibits p53-triggered apoptosis but not growth arrest. 756 60

CD19 receptor is expressed at high levels on human B-lineage lymphoid cells and is physically associated with the Src protooncogene family protein-tyrosine kinase Lyn. Recent studies indicate that the membrane-associated CD19-Lyn receptor-enzyme complex plays a pivotal role for survival and clonogenicity of immature B-cell precursors from acute lymphoblastic leukemia patients, but its significance for mature B-lineage lymphoid cells (e.g., B-lineage lymphoma cells) is unknown. CD19-associated Lyn kinase can be selectively targeted and inhibited with B43-Gen, a CD19 receptor-specific immunoconjugate containing the naturally occurring protein-tyrosine kinase inhibitor genistein (Gen). We now present experimental evidence that targeting the membrane-associated CD19-Lyn complex in vitro with B43-Gen triggers rapid apoptotic cell death in highly radiation-resistant p53-Bax- Ramos-BT B-lineage lymphoma cells expressing high levels of Bcl-2 protein without affecting the Bcl-2 expression level. The therapeutic potential of this membrane-directed apoptosis induction strategy was examined in a scid mouse xenograft model of radiation-resistant high-grade human B-lineage lymphoma. Remarkably, in vivo treatment of scid mice challenged with an invariably fatal number of Ramos-BT cells with B43-Gen at a dose level < 1/10 the maximum tolerated dose resulted in 70% long-term event-free survival. Taken together, these results provide unprecedented evidence that the membrane-associated anti-apoptotic CD19-Lyn complex may be at least as important as Bcl-2/Bax ratio for survival of lymphoma cells.
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PMID:Membrane-associated CD19-LYN complex is an endogenous p53-independent and Bc1-2-independent regulator of apoptosis in human B-lineage lymphoma cells. 756 75

The t(11;14)(q13;q32) translocation, which juxtaposes the BCL1 oncogene with the Ig heavy chain locus, has been associated with an uncommon subtype of non-Hodgkin's lymphoma (NHL) termed mantle cell lymphoma (MCL). To date, no molecular marker that serves as an indicator of tumor progression or clinical prognosis has been described for NHLs with this translocation. We examined a panel of NHLs with t(11;14) for overexpression of p53 and correlated the results with single-strand conformation polymorphism (SSCP) analysis, karyotypic features, and clinical course. NHLs with t(11;14) were identified from 30 patients. The diagnosis was MCL for 23 of 30, small lymphocytic lymphoma for 4 of 30, and diffuse large-cell lymphoma for 3 of 30 cases. The results of immunohistochemistry analysis using a monoclonal anti-p53 antibody on paraffin-embedded specimens were compared with the SSCP data, the tumor karyotypes, and clinical course of each patient. DNA sequencing of exons was performed on cases that showed conformational changes by SSCP analysis. NHLs from 5 of 23 patients with MCL were positive for p53 overexpression. Deletions of chromosome 17p were identified in 2 of 30 cases, both of which were MCLs showing p53 overexpression. Two of the five MCLs with p53 overexpression showed evidence for TP53 mutations. None of the 18 MCLs negative for p53 overexpression showed conformational changes by SSCP. For these 18 patients with MCLs that did not overexpress p53, the median survival was 63 months, compared with 12 months for the 5 patients with MCLs positive for p53 overexpression (P < .001). These results suggest that p53 overexpression in MCL with t(11;14)(q13;q32) may serve as a marker of poor prognosis.
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PMID:p53 overexpression as a marker of poor prognosis in mantle cell lymphomas with t(11;14)(q13;q32). 757 80

A number of properties of the cancer-related genes c-myc and p53 suggest that they might collaborate to induce tumorigenesis. To test this notion, we produced doubly heterozygotic mice bearing disrupted p53 alleles and a fusion transgene consisting of the mouse mammary tumor virus (MMTV) LTR and the oncogene c-myc. Mice bearing both the MMT/c-myc transgene and a single p53- allele develop very aggressive pre-T- and T-cell lymphomas with a significantly shorter latency than mice carrying either the p53- allele or the c-myc transgene alone. Moreover, every lymphoma occurring in these animals has lost or suffers an inactivation of its wild type p53 allele indicating that loss of p53 activity is necessary for this c-myc-accelerated lymphomagenesis. Nonetheless, p53 inactivation and expression of the MMTV/c-myc transgene are not sufficient for lymphoid transformation. Tumors that arise in homozygous p53- mice carrying the c-myc transgene are monoclonal, suggesting that at least one additional event is necessary for their transformation. Moreover, since mice bearing only the MMTV/c-myc transgene predominantly develop mammary carcinomas, it was surprising that the p53- allele failed to accelerate the incidence of mammary carcinomas. Further, in contrast to the lymphomas, only one in four mammary tumors that arose in the double heterozygotic mice had lost its wild type p53 allele. Apparently cell context influences the ability of c-myc and p53- to cooperate in inducing oncogenesis.
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PMID:The MMTV/c-myc transgene and p53 null alleles collaborate to induce T-cell lymphomas, but not mammary carcinomas in transgenic mice. 762 26

Transformation in follicular lymphoma represents an abrupt transition in tumor biology. The protein product of the bcl-2 oncogene is overexpressed in most follicular lymphomas and inhibits apoptosis. The protein product of the p53 oncogene prevents cell proliferation and induces apoptosis and is overexpressed in the dysfunctional (mutated) form. We studied 15 transformed lymphomas (large cell type), 7 follicular lymphomas before transformation and 2 control groups of follicular center cell lymphomas with no evidence of transformation (9 small cleaved cell and 10 de novo large cell lymphomas). High p53 expression (> or = 45% cells) was detected by immunostaining in 9/15 transformed lymphomas as compared with 0/10 de novo large cell lymphomas and 1/7 follicular lymphomas. Overexpression of bcl-2 (> or = 50% cells) was similar in transformed (11/15) and de novo large cell lymphomas (6/10). The apoptotic index was high (> or = 2%) in all transformed and large cell lymphomas and low in all follicular lymphomas and in the control group of small cleaved cell lymphomas. The apoptotic index in the transformed lymphomas appeared to be independent of bcl-2 expression and was sometimes paradoxically high in the presence of both p53 and bcl-2 overexpression. The apoptotic index was weakly associated with bcl-2 expression in de novo large cell lymphomas. Expression of p53 did not correlate with proliferation index. Our results indicate that p53 overexpression is a specific step associated with transformation and may occur shortly before it. This is not seen in de novo large cell lymphoma. Furthermore, the high apoptotic index in transformed lymphomas often occurs despite overexpression of bcl-2 and p53, implying that other factors may induce apoptosis in these tumors.
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PMID:Transformation of follicular lymphoma. Expression of p53 and bcl-2 oncoprotein, apoptosis and cell proliferation. 763 41


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