Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of P53, Bcl-2, Bax, Bag-1, and Mcl-1 proteins in CD5/CD20-positive B-chronic lymphocytic leukemia (B-CLL) cells from 30 typical CLL patients was evaluated before and after 48 h of incubation with 10(-6) M fludarabine using multiparametric flow cytometric analysis. Protein expression was correlated with annexin V expression, Rai modified clinical staging, lymphocyte doubling time, and previous treatment. Our main goal was to determine the predictive value of these proteins in CLL cells in terms of disease evolution. Bcl-2 expression decreased from a median fluorescence index (MFI) of 331.71 +/- 42.2 to 245.81 +/- 52.2 (P < 0.001) after fludarabine treatment, but there was no difference between viable cells (331.57 +/- 44.6 MFI) and apoptotic cells (331.71 +/- 42.2 MFI) before incubation (P = 0.859). Bax expression was higher in viable cells (156.24 +/- 32.2 MFI) than in apoptotic cells (133.56 +/- 35.7 MFI) before incubation, probably reflecting defective apoptosis in CLL (P = 0.001). Mcl-1 expression was increased in fludarabine-resistant cells and seemed to be a remarkable protein for the inhibition of the apoptotic process in CLL (from 233.59 +/- 29.8 to 252.04 +/- 35.5; P = 0.033). After fludarabine treatment, Bag-1 expression was increased in fludarabine-resistant cells (from 425.55 +/- 39.3 to 447.49 +/- 34.5 MFI, P = 0.012), and interestingly, this higher expression occurred in patients who had a short lymphocyte doubling time (P = 0.022). Therefore, we could assume that Bag-1 expression in such situation might identify CLL patients who will need treatment earlier.
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PMID:Fludarabine induces apoptosis in chronic lymphocytic leukemia--the role of P53, Bcl-2, Bax, Mcl-1, and Bag-1 proteins. 1650 12

The clinical course of chronic lymphocytic leukemia is variable. While some patients have indolent disease, others require aggressive treatment within a short time after diagnosis. Differences in the expression of proteins regulating cell cycle and apoptosis may be responsible for the heterogeneous course of the disease. Recently, protein ZAP 70 [zeta-chain (T-cell receptor) associated protein kinase 70 kDa] has been found to be differentially expressed within two biologic subgroups, characterized by the presence or absence of somatic mutations in specific immunoglobulin heavy-chain variable region genes. In the present work, we analyzed highly purified B-CLL cells from 60 patients for ZAP 70 expression and the expression of cyclin E, bcl-2, bax, and mcl-1 as well as the ratios of bcl-2/bax and mcl-1/bax. The results indicate that cyclin E is expressed significantly higher in ZAP 70-positive as in ZAP 70-negative samples. We did not observe significant differences within the expression of Bcl-2 family member proteins. We conclude that higher cyclin E expression in samples of ZAP 70-positive patients may reflect a larger proliferating compartment in vivo compared to ZAP 70-negative patients and that cyclin E may add prognostic information in this context for patients with B-CLL.
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PMID:Cyclin E but not bcl-2, bax or mcl-1 is differentially expressed in ZAP 70-positive and ZAP 70-negative B-CLL cells. 1653 1

Several groups have reported in recent years that members of the plant stress hormones family of jasmonates, and some of their synthetic derivatives, exhibit anti-cancer activity in vitro and in vivo. Jasmonates increased the life span of EL-4 lymphoma-bearing mice, and exhibited selective cytotoxicity towards cancer cells while sparing normal blood lymphocytes, even when the latter were part of a mixed population of leukemic and normal cells drawn from the blood of chronic lymphocytic leukemia (CLL) patients. Jasmonates join a growing number of old and new cancer chemotherapeutic compounds of plant origin. Three mechanisms of action have been proposed to explain the anti-cancer activity of jasmonates. These include: (1) The bio-energetic mechanism-jasmonates induce severe ATP depletion in cancer cells via mitochondrial perturbation; (2) The re-differentiation mechanism-jasmonates induce re-differentiation in human myeloid leukemia cells via mitogen-activated protein kinase (MAPK) activity; (3) The reactive oxygen species (ROS)-mediated mechanism-jasmonates induce apoptosis in lung carcinoma cells via the generation of hydrogen peroxide, and pro-apoptotic proteins of the Bcl-2 family. Several similarities between the effects of jasmonates on plant and cancer cells have been recorded, suggesting that additional analysis of jasmonate effects in plant cells may contribute to a deeper understanding of the anti-cancer actions of these compounds. Those similarities include: induction of cell death, suppression of proliferation and cell cycle arrest, MAPK induction, ROS generation, and enhancement of heat-shock proteins (HSP) expression. Finally, jasmonates can induce death in drug-resistant cells. The drug resistance was conferred by either p53 mutation or P-glycoprotein (P-gp) over-expression. In summary, the jasmonate family of novel anti-cancer agents presents new hope for the development of cancer therapeutics, which should attract further scientific and pharmaceutical interest.
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PMID:Jasmonates in cancer therapy. 1660 Apr 75

Drug development in human chronic lymphocytic leukemia (CLL) has been limited by lack of a suitable animal model to adequately assess pharmacologic properties relevant to clinical application. A recently described TCL-1 transgenic mouse develops a chronic B-cell CD5(+) leukemia that might be useful for such studies. Following confirmation of the natural history of this leukemia in the transgenic mice, we demonstrated that the transformed murine lymphocytes express relevant therapeutic targets (Bcl-2, Mcl-1, AKT, PDK1, and DNMT1), wild-type p53 status, and in vitro sensitivity to therapeutic agents relevant to the treatment of human CLL. We then demonstrated the in vivo clinical activity of low-dose fludarabine in transgenic TCL-1 mice with active leukemia. These studies demonstrated both early reduction in blood-lymphocyte count and spleen size and prolongation of survival (P = .046) compared with control mice. Similar to human CLL, an emergence of resistance was noted with fludarabine treatment in vivo. Overall, these studies suggest that the TCL-1 transgenic leukemia mouse model has similar clinical and therapeutic response properties to human CLL and may therefore serve as a useful in vivo tool to screen new drugs for subsequent development in CLL.
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PMID:Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. 1667 Feb 63

To investigate the expressions of proliferative antigen Ki-67 and apoptosis-antagonizing protein Bcl-2 in patients with chronic lymphocytic leukemia (CLL) and their clinical significance, immunohistochemistry method was used for detection of Ki-67 and Bcl-2 in bone marrow or peripheral blood of 29 patients with CLL. The results showed that the level of Ki-67 expression in advanced stage of CLL was higher than that in early stage of CLL and there was significant difference between these stages of CLL, but there was no significant difference between expression levels of Bcl-2 in two stages. The survival time in the group with Ki-67 expression < or = 8% was longer than that in the group of Ki-67 > 8%, and there was no significant difference of survival time between high and low groups in terms of Bcl-2 expression. It is concluded that detection of Ki-67 antigen and Bcl-2 protein for CLL patients can reflect the status of proliferation activity and apoptosis suppression of leukemia cells in patients; the level of Ki-67 expression closely correlate with the Binet stage and prognosis of CLL.
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PMID:[Expressions of ki-67 and bcl-2 in 29 cases of chronic lymphocytic leukemia and their clinical significance]. 1680 Sep 21

Bcl-2 plays a key role in the regulation of apoptosis. We investigated the role of a novel regulatory single-nucleotide polymorphism (-938C>A) in the inhibitory P2 BCL2 promoter in B-cell chronic lymphocytic leukemia (B-CLL). The -938C allele displayed significantly increased BCL2 promoter activity and binding of nuclear proteins compared with the A allele. Concomitantly, Bcl-2 protein expression in B cells from CLL patients carrying the -938 AA genotype was significantly increased compared with CC genotypes. Genotype distribution between 123 CLL patients (42 AA, 55 AC, 26 CC) and 120 genotyped healthy controls (36 AA, 63 AC, 21 CC) was not significantly different, suggesting that genotypes of this polymorphism do not increase the susceptibility for B-CLL. However, median time from first diagnosis to initiation of chemotherapy and median overall survival were significantly shorter in patients with -938AA genotype (38 and 199 months, respectively) compared with AC/CC genotypes (120 and 321 months, respectively; P = .008 and P = .003, respectively). Multivariable Cox regression identified the BCL2-938AA genotype as an independent prognostic factor for the time to first treatment (hazard ratio [HR] 1.9; P = .034) together with disease stage at diagnosis (HR 2.5; P = .004) and ZAP-70 status (HR 3.0; P = .001). The BCL2-938AA genotype is associated with increased Bcl-2 expression and a novel unfavorable genetic marker in patients with B-CLL.
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PMID:Association of a novel regulatory polymorphism (-938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia. 1815 4

Glucocorticoids induce apoptosis in chronic lymphocytic leukemia (CLL) cells through a caspase-dependent mechanism. However, their mechanism of action remains unknown. We have studied the regulation of the proapoptotic BH3-only Bcl-2 interacting mediator of cell death (BIM) in CLL cells. We demonstrate that glucocorticoids upregulate BIM at protein and mRNA levels. We have investigated the ability of different survival signals, such as 12-O-tetradecanoylphorbol 13-acetate (TPA), stromal cell-derived factor-1alpha (SDF-1alpha), interleukin 4 (IL-4) and B-cell receptor (BCR) activation, to influence the levels of BIM and its induction by glucocorticoids. TPA downregulates BIM(EL) by extracellular signal-regulated kinase (ERK)-mediated BIM phosphorylation and further proteasome-mediated degradation. However, SDF-1alpha and BCR activation induce transient BIM phosphorylation, without protein degradation. Proteasome inhibitors do not modify the levels of BIM with respect to untreated cells. However, they induce apoptosis and inhibit TPA-induced BIM(EL) degradation, leading to its accumulation. In conclusion, the results implicate BIM in glucocorticoid-induced apoptosis in CLL cells. BIM(EL) phosphorylation through the ERK pathway targets the protein for proteasomal degradation.
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PMID:Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells. 1715 1

B-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells that are resistant to apoptosis as a result of bcl2 oncogene overexpression. Studies were done to determine the mechanism for the up-regulation of bcl-2 protein observed in CD19+ CLL cells compared with CD19+ B cells from healthy volunteers. The 11-fold higher level of bcl-2 protein in CLL cells was positively correlated with a 26-fold elevation in the cytosolic level of nucleolin, a bcl2 mRNA-stabilizing protein. Measurements of the bcl2 heterogeneous nuclear/bcl2 mRNA (hnRNA)/mRNA ratios and the rates of bcl2 mRNA decay in cell extracts indicated that the 3-fold higher steady-state level of bcl2 mRNA in CLL cells was the result of increased bcl2 mRNA stability. Nucleolin was present throughout the nucleus and cytoplasm of CLL cells, whereas in normal B cells nucleolin was only detected in the nucleus. The addition of recombinant human nucleolin to extracts of normal B cells markedly slowed the rate of bcl2 mRNA decay. SiRNA knockdown of nucleolin in MCF-7 cells resulted in decreased levels of bcl2mRNA and protein but no change in beta-actin. These results indicate that bcl-2 overexpression in CLL cells is related to stabilization of bcl2 mRNA by nucleolin.
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PMID:Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA. 1717 26

We explored the relationship between the cytogenetic/biologic characteristics of B-chronic lymphocytic leukemia (B-CLL) cells and their tendency to undergo spontaneous or fludarabine-induced apoptosis in vitro. B cells from 36 B-CLL patients were incubated with or without fludarabine for 48 h. Apoptosis was determined by two assays: annexin V staining and DNA staining. Fluorescence in situ hybridization was used for detection of trisomy 12, 11q deletion, and 17p deletion. Bcl-2 and CD38 expressions were determined by flow cytometry. Five patients had 17p deletion, 6 had trisomy 12, and another 6 had 11q deletion. B-CLL cells with 17p deletion had significant resistance to apoptosis induced by fludarabine and a slight spontaneous resistance to apoptosis. Bcl-2 and CD38 were not associated with in vitro spontaneous and fludarabine-induced apoptosis. In conclusion, 17p deletion, which causes loss of p53 gene, is associated with resistance to fludarabine-induced apoptosis in vitro. New treatment modalities should be tried in B-CLL patients with 17p deletion.
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PMID:17p Deletion is associated with resistance of B-cell chronic lymphocytic leukemia cells to in vitro fludarabine-induced apoptosis. 1732 77

The incidence of follicular lymphoma in Saudi Arabia is very low compared to that in Western countries. We analyzed 22 diagnosed cases, based on conventional morphology examination and immunohistochemistry, to detect the Bcl-2 gene rearrangement by polymerase chain reaction (PCR). The DNA was extracted from formalin-fixed paraffin-embedded lymph node tissues by the standard xylene treatment and proteinase K digestion method. Rearrangement of the major breakpoint region was evident in 8 of the 22 cases (36%), determined by visualization of a discrete band hybridized with a chemiluminescence-labeled specific probe. Although the number of cases is small, we believe it denotes a normal detection rate for PCR analysis, using DNA isolated from fixed tissue. With the exception of follicular lymphoma, non-Hodgkin's lymphoma (NHL) analyzed included diffuse large cell lymphoma, lymphoblastic lymphoma, chronic lymphocytic leukemia, mucosa-associated lymphoid tissue and mantle zone lymphomas. No Bcl-2 gene rearrangement was detected in any of these cases. No evidence of Bcl-2 minor cluster sequence gene rearrangement was detected in any of the 38 NHL cases analyzed.
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PMID:Detection of BCL-2 gene rearrangement in follicular lymphoma by polymerase chain reaction and chemiluminescence technique. 1735 94


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