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)

P53 is known as a determinant of cellular responses to DNA damage, including apoptosis, cell cycle arrest, and DNA repair. Its role is most easily understood in the context of Burkitt lymphoma and other apoptosis-prone cell types. A number of epithelial cancer cell types, by contrast, exhibit a higher threshold for apoptosis induction in response to DNA damage. In fact, p53 mediates DNA repair and protective responses in the latter cell types, in some cases p53-deficient cells being more sensitive to DNA damage, antithetical to the situation in Burkitt lymphoma and other apoptosis-prone cell types. Ultraviolet light, cisplatin, and nitrogen mustards produce damage that is repaired by a p53-regulated pathway. Here, we explore the sensitivity of the platinum compound oxaliplatin and thio-TEPA (N, N', N", triethylenethiophosphoramide), a cancer chemotherapeutic agent that produces largely base damage, in p53-defective cells. This work demonstrates that the contribution of p53 temporally correlates with DNA repair pathways to produce a resistant phenotype, while the p53-defective cells are more sensitive to certain DNA-damaging chemotherapeutic agents.
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PMID:Sensitivity of p53-deficient cells to oxaliplatin and thio-TEPA (N, N', N" triethylenethiophosphoramide). 1205 67

The Epstein-Barr virus (EBV) transforms B cells in part by inhibiting the cellular apoptotic programme. This is also observed when Burkitt lymphoma cell lines are infected with EBV. Induction of apoptosis is one of the mechanisms by which fludarabine inhibits the growth of cells with low proliferative capacity. This compound can also inhibit several other mechanisms in the cell, including inhibition of the synthesis of factors such as STAT1. To analyse the relationship between EBV status, fludarabine-induced apoptosis, and transcription factors we studied the EBV-negative Burkitt lymphoma cell line BL2, its EBV-infected counterpart BL2.B95.8 and the EBV-transformed cell line PRI. The BL2 cell line was found to be very sensitive to fludarabine. The BL2.B95.8 and PRI cells were both resistant but the latter to a lesser extent. In the PRI cells fludarabine activated p53, but not in the BL2.B95.8 cells in which the p53 pathway is inactivated. We observed that this inactivation results in part from the lack of expression of the MDM2 inhibitor p14ARF. Conversely, there was a substantial constitutive activation of STAT1, and not of the other STATs, in the BL2.B95.8 cells and a modest one in the PRI cells. Furthermore, expression of STAT1 was significantly reduced by fludarabine treatment in the PRI cells, but not in the BL2.BL95.8 cells. Finally, the expression of p21WAF1/CIP1 was detected only in the BL2.B95.8 and PRI cells. This protein, known to play a role in cell survival, may therefore be involved in the resistance of the BL2.B95.8 cells to fludarabine.
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PMID:Resistance to fludarabine-induced apoptosis in Epstein-Barr virus infected B cells. 1208 25

Disruption of the physiologic balance between cell proliferation and death is a universal feature of all cancers. In general terms, human B-cell lymphomas can be subdivided into 2 main groups, low- and high-growth fraction lymphomas, according to the mechanisms through which this imbalance is achieved. Most types of low-growth fraction lymphomas are initiated by molecular events resulting in the inhibition of apoptosis, such as translocations affecting BCL2, in follicular lymphoma, or BCL10 and API2/MLT1, in mucosa-associated lymphoid tissue (MALT) lymphomas. This results in cell accumulation as a consequence of prolonged cell survival. In contrast, high-growth fraction lymphomas are characterized by an enhanced proliferative activity, as a result of the deregulation of oncogenes with cell cycle regulatory functions, such as BCL6, in large B-cell lymphoma, or c-myc, in Burkitt lymphoma. Low- and high-growth fraction lymphomas are both able to accumulate other alterations in cell cycle regulation, most frequently involving tumor suppressor genes such as p16(INK4a), p53, and p27(KIP1). As a consequence, these tumors behave as highly aggressive lymphomas. The simultaneous inactivation of several of these regulators confers increased aggressivity and proliferative advantage to tumoral cells. In this review we discuss our current knowledge of the alterations in each of these pathways, with special emphasis on the deregulation of cell cycle progression, in an attempt to integrate the available information within a global model that describes the contribution of these molecular changes to the genesis and progression of B-cell lymphomas.
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PMID:Cell cycle deregulation in B-cell lymphomas. 1239 83

We report five cases of Burkitt lymphoma arising in organ transplant recipients. There were four men and one woman with a mean age of 35 years. All were solid organ recipients with three renal, one liver, and one double lung transplantation. The time interval between organ transplantation and lymphoma averaged 4.5 years. Patients typically presented with high-stage disease with generalized lymphadenopathy and bone marrow involvement. Histology showed classic Burkitt lymphoma or atypical variant/Burkitt-like morphology. C-MYC rearrangement, including three cases with immunoglobulin heavy chain and two cases with lambda light chain, and Epstein-Barr virus were detected in all the cases. Additional chromosomal abnormalities were present in two of three cases and p53 mutation was found in one of three cases. Aberrant genotype and phenotype were frequently encountered, including minor monoclonal or oligoclonal T-cell populations and undetectable surface immunoglobulin light chain expression. Four patients received antilymphoma regimens, with combination chemotherapy (three patients) and/or Rituximab (three patients), in addition to reduction of immunosuppression. All four patients achieved complete remission. We conclude that posttransplant Burkitt lymphoma represents a characteristic clinicopathologic entity and occurs later after transplantation. Genotypic and phenotypic aberrations are often present. Rituximab may be an effective alternative to conventional combination chemotherapy in the treatment of a posttransplant Burkitt lymphoma.
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PMID:Burkitt lymphoma arising in organ transplant recipients: a clinicopathologic study of five cases. 1276 87

The translocation between chromosomes 2 and 8, t(2;8), is well known for its strong association with high-grade Burkitt lymphoma. However, the significance of this translocation in indolent lymphoproliferative disorders is not clear. We present the case of a 75-year-old white male with left upper quadrant abdominal pain, splenomegaly, and an elevated white cell count of 30.3x10(9) cells/L (84% large lymphoid cells with scanty cytoplasm and prominent central nucleoli). Immunophenotyping revealed a clonal B-cell population coexpressing CD5, CD19, and CD20 with weak CD23 and CD25 and very weak, restricted, surface lambda. The cytogenetic analysis showed all 20 cells with t(2;8)(p12;q24.3). In addition, four of the 20 cells also showed a second translocation: t(12;17)(p13;q21). Molecular analysis using c-myc and p53 probes showed normal results with no indication of amplification of C-MYC or deletion of TP53. The patient was managed as an indo-lent/low-grade lymphoproliferative disorder with excellent response to eight cycles of fludarabine.
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PMID:An indolent B-cell lymphoma with t(2;8)(p12;q24) abnormality and absence of C-MYC amplification and TP53 deletion. A new variant? 1281 Feb 61

To clarify the clinical and genetic features of Burkitt lymphoma with or without leukemic presentation, we have conducted clinical, cytogenetic, and genetic studies. Of 40 Japanese patients with Burkitt lymphoma examined by cytogenetic and/or fluorescence in situ hybridization analysis or Southern blot analysis using MYC probes, 35 patients had t(8;14) translocations, and 5 had t(8;22). Breakpoints were located far upstream of MYC in 4 (12%) of 33 tumors with t(8;14), and Epstein-Barr virus infection was found in 3 (8%) of 40 tumors. These findings are similar to those reported for non-Japanese patients with the sporadic form of Burkitt lymphoma. Clinical and genetic characteristic were compared for 30 patients presenting with lymphoma and 10 presenting with leukemia. The overall survival was shorter in aggressively treated leukemia patients than in aggressively treated lymphoma patients (P = .003); however, the incidence rates of TP53 mutation, p16INK4a deletion, and p15INK4b deletion that were found in 6 (15%) of 40,3 (9%) of 35, and 2 (6%) of 35 tumors, respectively, were similar between the 2 subtypes. Thus, the present study has shown the different prognoses for the 2 subtypes of Burkitt lymphoma but has failed to clarify the genetic backgrounds that may explain the different outcomes.
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PMID:Clinical and genetic characteristics of Japanese Burkitt lymphomas with or without leukemic presentation. 1284 88

SAP is an adaptor molecule with one SH2 domain and it is expressed in activated T and NK cells, where it is required for the appropriate signaling from the SLAM family of surface receptors. Deleted or mutated SAP genes that encode functionally defective protein are associated with the X-linked lymphoproliferative disease (XLP). This primary immunodeficiency is characterized by extreme sensitivity to Epstein-Barr virus (EBV) infection, dysgammaglobulinemia and a high rate of lymphoma development. The vigorous T- and B-cell proliferation that follows EBV infection and the high incidence of lymphomas (30%) in XLP patients might reflect functional defects in cell cycle and/ or apoptosis control. Our experiments show that SAP is a target of p53. In Burkitt lymphoma (BL) lines transfected with a temperatur-sensitive (ts) p53, SAP mRNA and protein expression was dependent on wild-type (wt) p53. Activation of endogenous wt p53 in BLs and lymphoblastoid cell lines led to the induction of SAP and this was inhibited by the specific p53 inhibitor pifithrin-alpha. Cell lines that carried mutant p53 did not express SAP under similar conditions. Moreover, we have shown binding of wt p53 to the promoter region of SAP by ChIP assay. Our results suggest that SAP contributes to the execution of some p53 functions.
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PMID:Wild-type p53 activates SAP expression in lymphoid cells. 1537 26

The p53 tumor suppressor controls cell growth and survival through transcriptional regulation of gene expression. Previously, we found that the human telomerase reverse transcriptase (hTERT) gene is downregulated by p53. To investigate if hTERT downregulation has a role in p53-dependent apoptosis, we tested if constitutive expression of telomerase could inhibit p53-induced apoptosis. Here we show that constitutive hTERT expression results in increased survival following activation of exogenous temperature-sensitive p53 in BL41 Burkitt lymphoma cells. Similarly, constitutive hTERT expression inhibited wild-type p53-dependent apoptosis in response to mitomycin C or 5-fluorouracil in HCT116 colon carcinoma cells carrying endogenous p53. A telomerase-inactive hTERT mutant was equally efficient in antagonizing p53-induced apoptosis. These findings support the notion that hTERT has antiapoptotic activity and demonstrate that p53-mediated downregulation of hTERT is critical for efficient p53-dependent apoptosis.
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PMID:hTERT antagonizes p53-induced apoptosis independently of telomerase activity. 1560 86

We used gene targeting in mice to insert a His(6)-tagged mouse c-Myc cDNA, Myc(His), head to head into the mouse immunoglobulin heavy-chain locus, Igh, just 5' of the intronic enhancer, Emu. The insertion of Myc(His) mimicked both the human t(8;14)(q24;q32) translocation that results in the activation of MYC in human endemic Burkitt lymphomas and the homologous mouse T(12;15) translocation that deregulates Myc in certain mouse plasmacytomas. Beginning at the age of 6 months, Myc(His) transgenic mice developed B-cell and plasma neoplasms, such as IgM(+) lymphoblastic B-cell lymphomas, Bcl-6(+) diffuse large B-cell lymphomas, and CD138(+) plasmacytomas, with an overall incidence of 68% by 21 months. Molecular studies of lymphoblastic B-cell lymphoma, the most prevalent neoplasm (50% of all tumors), showed that the lymphomas were clonal, overexpressed Myc(His), and exhibited the P2 to P1 promoter shift in Myc expression, a hallmark of MYC/Myc deregulation in human endemic Burkitt lymphoma and mouse plasmacytoma. Only 1 (6.3%) of 16 lymphoblastic B-cell lymphomas contained a BL-typical point mutation in the amino-terminal transactivation domain of Myc(His), suggesting that most of these tumors are derived from naive, pregerminal center B cells. Twelve (46%) of 26 lymphoblastic B-cell lymphomas exhibited changes in the p19(Arf)-Mdm2-p53 tumor suppressor axis, an important pathway for Myc-dependent apoptosis. We conclude that Myc(His) insertion into Igh predictably induces B-cell and plasma-cell tumors in mice, providing a valuable mouse model for understanding the transformation-inducing consequences of the MYC/Myc-activating endemic Burkitt lymphoma t(8;14)/plasmacytoma T(12;15) translocation.
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PMID:Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice. 1573 16

The human Burkitt lymphoma Daudi cell line expresses constitutively active nuclear factor kappaB (NF-kappaB) in the nucleus in spite of high levels of inhibitor kappaB-alpha (IkappaB-alpha) in the cytoplasm. The antiproliferative response of these cells to interferon-alpha (IFN-alpha) correlated with the inhibition of the constitutive NF-kappaB activity by the cytokine. The present study shows that IFN-alpha caused an increase in p53 level, inhibited cell proliferation by [(3)H]thymidine incorporation, and stimulated cytotoxicity and apoptosis by PARP-cleavage in the Daudi cells. In order to study the relationship between the constitutively active NF-kappaB and IkappaB-alpha, a dominant negative mutant IkappaB-alpha (IkappaB-alphaDN), lacking the N-terminal 36 amino acids required for the activation of NF-kappaB by tumor necrosis factor-alpha (TNF-alpha), was expressed in the Daudi cells. The expression of IkappaB-alphaDN protein did not inhibit the constitutive NF-kappaB activity, but it inhibited cell proliferation, antiproliferative response to IFN-alpha, and phosphorylated mitogen activated protein kinase (p-MAPK) level. Thus, our results suggest that constitutive NF-kappaB activity in the human Burkitt lymphoma Daudi cells is maintained by a mechanism independent of IkappaB-alpha degradation, and that the IkappaB-alpha is involved in the proliferation of these cells, possibly through the MAP kinase pathway. Therefore, in addition to IFN-alpha treatment, both NF-kappaB and IkappaB-alpha may be used as drug targets for inhibiting cell proliferation in the lymphomas.
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PMID:Relationship between constitutive nuclear factor-kappaB (NF-kappaB) and inhibitor kappaB-alpha (IkappaB-alpha) in an interferon-alpha-sensitive human Burkitt lymphoma cell line. 1597 56


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