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)

We previously found that cases of typical B-chronic lymphocytic leukemia (CLL), atypical B-CLL with t(11;14) and mantle cell lymphomas characterized by rapid progression of the disease and resistance to therapy, had mutations of the TP53 gene. In this paper, abnormalities of the TP53 gene were investigated in two cases of prolymphocytic leukemia, one with t(11;14)(q13;q32), evolving from atypical CLL (patient 1), and one presenting as a de novo condition (patient 2). TP53 DNA was investigated by Southern blot and PCR-SSCP analysis, and TP53 expression was investigated by Northern blot analysis and immunocytochemistry. C-MYC and BCL-1/PRAD1 gene expression were also investigated. Restriction enzyme analysis of TP53 DNA in patient 1 showed alteration of fragments including exon I and intron I, and, in both patients, a specific loss of TP53 DNA. In patient 2, PCR direct sequencing showed in exon VII a 9 bp deletion including codons 252-254. In patient 1, TP53 RNA and protein were not found, indicating that the unusual 5' rearrangement has affected TP53 gene expression. By contrast, patient 2 exhibited detectable TP53 RNA and protein. Detectable but weak BCL-1/PRAD1 RNA was present in both patients, whereas C-MYC RNA expression was clearly present only in case 1. The presence of TP53 hemizygous mutations in both patients suggests that TP53 abnormalities may be important in the pathogenesis of prolymphocytic leukemia (PLL), and may possibly account for the frequent resistance to therapy observed in this disease.
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PMID:5' region and exon 7 mutations of the TP53 gene in two cases of B-cell prolymphocytic leukemia. 984 9

Indolent lymphomas are a markedly heterogeneous group of lymphoproliferative disorders including B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mantle cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma. The molecular pathophysiology of indolent lymphoma is characterized by distinct genetic pathways which selectively associate with different clinico-pathologic categories of the disease. At diagnosis, B-cell chronic lymphocytic leukemia frequently display deletions of 13q14, trisomy 12 and alterations of the ATM gene, whereas evolution to Richter's syndrome is associated with disruption of p53. Lymphoplasmacytoid lymphoma carries t(9;14) (p13;q32) in approximately 50% of cases, leading to the deregulated expression of the PAX-5 gene. Follicular lymphoma consistently harbors rearrangement of BCL-2. With time, a fraction of follicular lymphoma accumulates mutations of p53 and of p16 and evolves into a high grade lymphoma. MALT-lymphoma frequently associates with alterations of API2/MLT and, in some cases, of p53, BCL-6 and BCL-10. Studies of genotypic and phenotypic markers of histogenesis have shown that mantle cell lymphoma and a fraction of B-CLL/SLL derive from naive B-cells, whereas follicular lymphoma, lymphoplasmacytoid lymphoma and MALT-lymphoma originate from germinal center (GC) or post-GC B-cells. The identification of distinct genetic categories of indolent lymphoma may help in the therapeutic stratification of these disorders. In addition, genetic lesions of indolent lymphoma provide useful molecular markers for disease monitoring by high sensitivity techniques.
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PMID:Molecular pathophysiology of indolent lymphoma. 1068 15

p53 is a tumor suppressor gene encoding a nuclear phosphoprotein that plays an important role in the control of normal cell proliferation. We have tried to establish the value of the p53 protein expression in peripheral blood (PB) and/or bone marrow (BM) cells of patients with some hematological malignancies. A recently developed fixation/permeabilization method was modified for flow cytometric assessment of p53 protein expression using two anti-p53 monoclonal antibodies. p53 quantitation expressed as molecules of equivalent soluble fluorochrome per cell (MESF) providing valuable data contributing to a more precise definition of leukemic cells, was also applied. Our findings showed higher percentage of p53 expression in cells of AML patients at the time of diagnosis opposite to the controls. These data, in association with immunophenotype of cells, accompanied diagnosis of relapse or definition of remission after allogeneic BM transplantation. We observed also elevated levels of p53 protein at initial diagnosis of early B-ALL. According to our results quantitation of p53 protein allows better characterization of selected population of BM cells and should be used for the monitoring of blast persistence during and after therapy and might also be one of the methods to indicate early relapse. Percentage of p53 protein positivity varied in our group of B-CLL patients tested in connection with progression of disease. We documented also one case of Burkitt's lymphoma with high percentage of p53 positivity. Measurement of p53 protein expression by flow cytometry may be of clinical importance by indicating levels of positivity. Our results suggest, that p53 alteration is frequently involved at initial diagnosis of AML, in some T-cell disorders and on the contrary more frequently during early B-ALL relapse, in advanced stages of B-CLL and in Burkitt's lymphoma. p53 protein quantitation is of value to ascertain malignancy and provides additional parameter suitable for the evaluation of residual disease and for the monitoring of therapy.
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PMID:Flow cytometry of p53 protein expression in some hematological malignancies. 1073 66

Various genetic abnormalities are often found in B-CLL, but their relative importance in the pathogenesis and evolution of the disease has not been adequately clarified. We studied the expression of bcl-2 protein and the possible simultaneous occurrence of bcl-2 overexpression, trisomy 12 and the Rb1 and p53 gene deletions in 38 patients with B-CLL by combining immunophenotyping and dual color interphase FISH. We also looked for correlation between the genetic abnormalities and clinical parameters such as stage, disease duration from diagnosis to the time of study and overall survival. High expression of the bcl-2 protein was found in 76.3% of the patients (29/38). Trisomy 12 was found in 37% of cases (14/38) and Rb1 monoallelic gene deletion in 42% (16/38). The percentage of cells with hemizygous Rb1 deletion ranged from 13 to 18%. Monoallelic deletion of p53 was found in 29% of cases (11/38). The number of cells with only one signal ranged from 28 to 98%. Patients in stage A had on average, less than one abnormality, while patients in stage C had 2.6 abnormalities. Patients appeared to accumulate genetic abnormalities with time. Bcl-2 overexpression was found early in the course of the disease. Trisomy 12 appeared later, at about the same time as Rb1 deletion, but was not associated with adverse prognosis. Monoallelic deletion of p53 gene appeared rather late in the course of the disease and was associated with advanced stage. Despite the fact that more deaths occurred in the group of patients with three or four abnormalities and the presence of p53 gene deletion, differences in survival were not statistically significant, probably due to the limited number of patients in each group. A larger group of patients studied in a prospective manner will better clarify these issues in the future.
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PMID:Simultaneous detection of BCL-2 protein, trisomy 12, retinoblastoma and P53 monoallelic gene deletions in B-cell chronic lymphocytic leukemia by fluorescence in situ hybridization (FISH): relation to disease status. 1078 95

Nitric oxide (NO) exerts contrasting effects on apoptosis, depending on its concentration, flux and cell type. In some situations, NO activates the transduction pathways leading to apoptosis, whereas in other cases NO protects cells against spontaneous or induced apoptosis. The redox state of the cells appears to be a crucial parameter for the determination of the ultimate action of NO on cell multiplication and survival. Apoptosis is mostly associated with the delivery of NO by chemical donors and with myelomonocytic cells, whereas antiapoptotic effects seem to be related to the endogenous production of NO by NO synthases and is observed more frequently in cells of the B lymphocyte lineage. Pro-apoptotic effects are often observed when NO reacts with superoxide to produce the highly toxic peroxynitrite. Through the induction of damages to DNA, NO stimulates the expression of enzymes and transcription factors involved in DNA repair and modulation of apoptosis, such as the tumor suppressor p53. The latter molecule transactivates the expression of pro-apoptotic genes, such as bax, and that of the cyclin-dependent kinase inhibitor p21, whereas it down-regulates the expression of the anti-apoptotic protein bcl-2. On the other hand, NO inactivates caspases through oxidation and S-nitrosylation of the active cystein, providing an efficient means to block apoptosis. Other protective effects of NO on apoptosis rely on the stimulation of cGMP-dependent protein kinase (PKG), modulation of the members of the bcl-2/bax family that control the mitochondrial pore transition permeability, induction of the heat shock protein HSP 70 and interaction with the ceramide pathway. A defect in the apoptotic process contributes to the accumulation of tumoral cells in leukemia, notably in B-CLL. A better knowledge of the targets of NO would provide efficient means to control cell apoptosis, and hence would possibly lead to the development of new therapeutic approaches for diseases where an alteration of apoptosis is involved.
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PMID:Mechanisms involved in the pro- and anti-apoptotic role of NO in human leukemia. 1099 17

We report a case of chronic lymphocytic leukaemia (CLL) with telomeric associations and a p53 intronic point mutation. Karyotypic analysis revealed clonal and non-clonal telomeric associations, accompanied by clonal cytogenetic abnormalities and also in isolation. The p53 mutation, which occurred at the invariant base pair -2 of the splice acceptor site in intron 7 resulted in the abolition of correct splicing of exon 7 to exon 8. Multiple aberrant splice products were characterized, all of which differed from wildtype in the DNA binding domain. Fluorescence in situ hybridization demonstrated that the clone retained two copies of the p53 gene and wild-type p53 transcript was detected on cloning of reverse transcriptase polymerase chain reaction (RT-PCR) product, indicating that one wild-type allele remained. However, a plasmid clone with correct splicing at the exon 7/8 boundary, but with a 21 bp deletion in exon 8, was also found at low frequency. This finding indicates clonal evolution, resulting in complete loss of wild-type p53. The intronic point mutation was not present in DNA extracted from cervical tissue indicating that it was a leukaemic phenomenon. This is the first case of an intronic point mutation to be reported in CLL. This mutation led to chaotic p53 expression and, interestingly, occurred in a case showing telomeric associations, a rare phenomenon in B-CLL.
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PMID:p53 intronic point mutation, aberrant splicing and telomeric associations in a case of B-chronic lymphocytic leukaemia. 1109 Dec 5

B-cell chronic lymphocytic leukemia (CLL) is the most common type of leukemia diagnosed in the Western Hemisphere and remains incurable with currently available therapy. In an attempt to identify new potential therapy for CLL, we explored the pre-clinical activity of gemcitabine in human B-CLL cells (n =11). Mononuclear cell isolates were exposed to varying concentrations of gemcitabine (0.01-100 microM) for 4, 24, and 96 h. Viability, as determined by the tetrazolium salt (MTT) assay, after a 4 h incubation with gemcitabine declined in 6 of 8 (75%) evaluable patients at a concentration < 30 microM (a physiologically attainable level), and 3 of 8 of the B-CLL cells had an LC50 (concentration where 50% loss of viability is observed) < 30 microM. At 4 days of drug exposure, 82% (9/11) of patients had an LC50 < 30 microM. Annexin-V/propidium iodine staining demonstrated apoptosis in CLL cells exposed to 30 microM of gemcitabine. Examination of changes in apoptosis related proteins demonstrated no significant change in bcl-2, bax or p53 protein expression with gemcitabine (23 microM) at 4, 24, or 48 h. These data demonstrate that gemcitabine has pre-clinical activity in B-CLL and supports its exploration as a single agent and in combination with other active agents in this disease.
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PMID:Gemcitabine demonstrates in vitro activity against human B-cell chronic lymphocytic leukemia. 1133 14

The p73 protein shares structural and functional similarities with the tumour-suppressor p53, but its role in neoplastic transformation is unknown. Alternative splicing leads to the expression of at least nine p73 C-terminal mRNA splice variants (alpha, beta, gamma, delta, epsilon, zeta, eta, eta1, theta). In this survey, we analyse the expression of p73 by real-time quantitative RT-PCR, its known C-terminal variants with an RT-PCR-Southern technique and by Western blot in samples of 51 patients with B-CLL, normal B lymphocytes from eight individuals, and five haematopoetic cell lines. p73alpha protein expression positively correlated with higher risk B-CLL stages (P = 0.046). Total p73 mRNA expression was higher (P = 0.01) and p73alpha protein more frequently detected (P = 0.008) in B-CLL compared with normal CD19+-B-lymphocytes. p73 C-terminal mRNA variants were expressed both in B-CLL and in normal B-lymphocytes, but their expression was biased since the gamma (P = 0.041), the theta (P < 0.001), and the eta variant (P = 0.033) prevailed in normal B-lymphocytes. In summary, we conclude that the accumulation of p73, the expression pattern of particular p73 variants and its link to progression may play a distinct role in the molecular pathology B-CLL.
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PMID:Overexpression of the p73 gene is a novel finding in high-risk B-cell chronic lymphocytic leukemia. 1152 6

Signal transduction and apoptosis in B-cell chronic lymphocytic leukemia (CLL) cells with a post-germinal center (GC) phenotype were studied. Specific activation of the cells was induced by a combination of soluble anti-CD40 monoclonal antibody and interleukin-4 (CD40/IL-4) and nonspecific activation with a combination of phytohemagglutinin, phorbol-12-myristate-13-acetate and ionomycin (chemical mixture). Less than 5% of these leukemia cells entered the cell cycle after activation, as indicated by the number of cells in G0/G1 phase. The protein tyrosine phosphorylation pattern and expression of the Bcl-2 protein were specific in ex vivo CLL cells of each individual patient. Expression of the p53 protein was not detectable in these leukemia cells. Cross-linking of the CD40/IL-4 receptors on CLL cells significantly upregulated phosphotyrosine proteins and the p53 protein. In the presence of chemical mixture, downregulated phosphotyrosine proteins were detected. Alterations in Bcl-2 expression were independent of cross-linking with CD40/IL-4 or chemical mixture. A high frequency of apoptotic cells was detected in cells that had downregulated phosphotyrosine proteins and Bcl-2 protein. There was no correlation between induction of apoptosis and expression of p53 protein. Our results suggest that apoptosis in resting leukemia cells could occur prior to the cell cycle progression. Alterations in phosphotyrosine proteins and Bcl-2 but not p53 might play an important role in the regulation of apoptosis in resting G0/G1 memory post-GC B-CLL cells.
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PMID:Significance of phosphotyrosine proteins, Bcl-2 and p53 for apoptosis in resting B-chronic lymphocytic leukemia (CLL) cells. 1177 86

In B-CLL, non-proliferating B cells accumulate due to defective apoptosis. Cytotoxic therapies trigger apoptosis and deregulation of apoptotic pathways contributes to chemoresistance. Loss of the apoptosis-promoting Bax has been implicated in resistance to cytotoxic therapy. We therefore evaluated ex vivo drug sensitivity of CLL, producing chemoresponse data which are prognostic indicators for B-CLL, in particular in the case of purine nucleoside analogs. To analyze the underlying mechanisms of drug resistance, we compared endogenous Bax and Bcl-2 expression to ex vivo response to eight drugs, and to survival in 39 B-CLL patients. We found that reduced Bax levels correlated well with ex vivo resistance to traditional B-CLL therapies - anthracyclines, alkylating agents and vincristine (all P < 0.04). Surprisingly, no such relationship was observed for the purine nucleoside analogs or corticosteroids (all P > 0.5). Mutational analysis of p53 could not explain the loss of Bax protein expression. Levels of Bcl-2 were not associated with sensitivity to any drug. In contrast to the ex vivo data, neither Bax or Bcl-2 expression nor doxorubicin sensitivity were associated with increased survival whereas sensitivity to fludarabine correlated with better overall survival (P = 0.031). These findings suggest that the resistance to purine nucleoside analogs and corticosteroids in B-CLL is due to inactivation of pathways different from those activated by anthracyclines, vinca alkaloids and alkylating agents and may be the molecular rationale for the efficacy of purine analogs in this disease.
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PMID:Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia. 1204 Apr 35


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