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)

A 2.8-kilobase major breakpoint region on chromosome segment 18q21 is the site of most t(14;18) translocations typical of human follicular lymphomas. Breaks are focused at the 5' end of joining (JH) regions of immunoglobulin (Ig) on chromosome 14, indicating that the translocation occurs at a pre-B-cell stage during attempted heavy (H) chain joining. A new gene from 18q21 (Bcl-2) is placed in the H chain locus creating a unique, translocation-specific JH;18q21 rearrangement that presumably represents a transformation event. In addition, normal Ig gene joining occurs in a H before light (L) chain and K before lambda cascade, creating ordered clonal markers. These serial markers were examined to determine if variations in Ig gene patterns during the natural history of lymphomas represent the emergence of truly separate neoplasms or heterogeneity of a single neoplasm. We examined 45 serial biopsies from 16 B follicular lymphoma patients; six cases showed variation in Ig gene patterns over time. Seven individuals had a detectable JH;18q21 rearrangement present, and it remained unchanged over 5-10 years. Further rearrangements of H chain genes occurred on the normal chromosome 14 within evolving subclones of the original tumor. Lambda L chains also underwent additional rearrangements in two instances, while K gene patterns remained unchanged. All variations in the normal H and L chain genes were 2 degrees rearrangements occurring at a mature B-cell stage following the initial successful rearrangement of a H and L chain. In contrast the t(14;18) breakpoint was conserved in each individual, indicating that evolving neoplastic subpopulations arose from a common clonal progenitor cell.
Cancer Res 1987 May 15
PMID:Clonal evolution of t(14;18) follicular lymphomas demonstrated by immunoglobulin genes and the 18q21 major breakpoint region. 303 7

Many genes are involved in cell cycle control, DNA repair and induction of cell death. Alterations in these genes have been responsible for the development of cancer as well as for resistance to cancer therapy. Recently, an emerging family of bcl2-like genes has been identified that plays a role in the regulation of cell death. Its members are highly conserved in several domains which have been shown to be important for homodimerization or heterodimerization. The ratio between BAX/BCL2 heterodimers and BAX/BAX homodimers appears to be pivotal in deciding the life of death of a cell. We recently detected mutations in evolutionary highly conserved domains of the bax gene in cell lines derived from hematologic malignancies. Similar artificially generated mutations in other bcl2-like family members bcl2, bclxl, or ced9 have been shown to alter their function. This suggests a role for bax mutations in the multi-step pathogenesis of hematological malignancies.
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PMID:Bax mutations in cell lines derived from hematological malignancies. 747 70

Modulation of apoptosis may influence resistance to chemotherapy and therefore affect the outcome of cancer treatment. Ovarian cancer, one of the most fatal malignancies in women, is often associated with drug resistance but the cellular pathways contributing to this effect remain obscure. We have found that Bcl-2 and p53, two proteins implicated in the control of apoptosis, are frequently expressed in fresh biopsies of primary ovarian carcinoma. Examination of Bcl-2 and p53 protein levels in pairs of cis-platin sensitive and resistant ovarian cell lines demonstrated that the resistant variants over-express Bcl-2 and/or p53, apparently due to progressive expansion of Bcl-2 and/or p53 positive subpopulations during the in vitro development of resistance. Exogenous expression of Bcl-2 or a temperature sensitive mutant p53 (ts p53) in the ovarian cell line A2780 resulted in protection from drug-induced apoptosis and a delay in drug-mediated S-phase arrest. Interestingly, p53 accumulation in response to DNA damage induced by different agents was significantly delayed and reduced in the Bcl-2 transfectants compared to the control A2780 line, suggesting that Bcl-2 may act upstream of the p53 pathway. Similarly, the induction of Bax mRNA and protein was also found to be delayed in the presence of Bcl-2. Overall, our data provide further evidence for cross-talk between Bcl-2, p53 and Bax and suggest that these genes are important determinants of drug-induced apoptosis thereby modulating resistance to chemotherapy.
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PMID:The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and Bcl-2. 747 41

Many cancers overexpress a member of the bcl-2 family of inhibitors of apoptosis. To determine the role of these proteins in maintaining cancer cell viability, an adenovirus vector that expresses bcl-xs, a functional inhibitor of these proteins, was constructed. Even in the absence of an exogenous apoptotic signal such as x-irradiation, this virus specifically and efficiently kills carcinoma cells arising from multiple organs including breast, colon, stomach, and neuroblasts. In contrast, normal hematopoietic progenitor cells and primitive cells capable of repopulating severe combined immunodeficient mice were refractory to killing by the bcl-xs adenovirus. These results suggest that Bcl-2 family members are required for survival of cancer cells derived from solid tissues. The bcl-xs adenovirus vector may prove useful in killing cancer cells contaminating the bone marrow of patients undergoing autologous bone marrow transplantation.
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PMID:A recombinant bcl-x s adenovirus selectively induces apoptosis in cancer cells but not in normal bone marrow cells. 747 29

Apoptosis, programmed cell death, was immunohistochemically determined in 55 samples of oesophageal squamous cell carcinoma using the BM1 Mab. Sections from patients not treated (group 1, n = 12) or preoperatively treated by chemotherapy (group 2, n = 11), radiation (group 3, n = 13) or both (group 4, n = 8), and 11 additional cases of high-grade dysplasia or early cancer were examined. Most of the apoptotic cells were BM1-positive and checked by TUNEL proved to be nick end positive. They accounted for 7 (11%), 19 (29%), 21 (32%) and 26 (38%) cells per field in those 4 groups respectively. Chemotherapy and/or radiation significantly increased the number of apoptotic cells as compared to controls (p = 0.029 and p = 0.029, respectively). To assess the implications of the oncogene expression in the apoptotic pathway, additional section stained with bcl2 and p53 were negative for bcl2 and were positive for p53 in 16 samples (37%). Overall, positive cases for p53 mutation showed a significantly decreased incidence of apoptotic cells (p = 0.03). These results suggest that in situ assessment of apoptotic response better correlates to the apoptosis induced by radiation than that by chemotherapy, that abnormalities of the p53 protein decrease the apoptotic response in oesophageal carcinoma, and that immunohistochemical analysis of p53 protein helps to determine the sensitivity to these anticancer agents.
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PMID:Assessment of apoptosis in oesophageal carcinoma preoperatively treated by chemotherapy and radiotherapy. 753 43

Selective induction of programmed cell death, apoptosis, may represent a new approach to the treatment of cancer. Apoptosis can be induced by the monoclonal antibody anti-APO-1 directed against the cell surface receptor APO-1, a member of the nerve growth factor (NGF) receptor/tumor necrosis factor (TNF) receptor superfamily. We determined APO-1 expression and sensitivity to anti-APO-1 mediated apoptosis in childhood acute lymphoblastic leukemia cells of T lymphocyte precursor phenotype (T-ALL). APO-1 was constitutively expressed by 21 of 30 T-ALL and by all T-ALL cell lines investigated. However, most APO-1 positive T-ALL were resistant to anti-APO-1 mediated apoptosis. Sensitivity to anti-APO-1 mediated apoptosis was independent of the density of APO-1 expression on the cell surface and independent of the amount of Bcl-2. Incubation of resistant T-ALL with the protein synthesis inhibitor cycloheximide reversed resistance and induced sensitivity to anti-APO-1 mediated apoptosis in most T-ALL. These data suggest that resistance to anti-APO-1 mediated apoptosis in T-ALL is maintained by an active cellular program. Reversion of resistance to sensitivity towards induction of apoptosis in tumors may provide a new basis for successful therapeutic intervention.
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PMID:Resistance to APO-1 (CD95) induced apoptosis in T-ALL is determined by a BCL-2 independent anti-apoptotic program. 753 14

The expression of bcl-2 was studied in normal ovaries and in ovarian tumours by immunohistochemical analysis. Normal epithelium was strongly stained in all nine examined ovaries. In comparison, all tumour groups showed a substantially decreased tumour cell expression of the same order of magnitude. Thus, benign tumour cells were weakly stained in two and unstained in two samples, while the remaining eight showed strong expression. Of ten borderline samples, one was unstained and five had weakly and four strongly bcl-2 positive tumour cells. Finally, 24 of 50 malignant tumours showed strong staining, while weak or no expression in tumour cells was found in 16 and 10 samples respectively. The reduced staining deviated significantly from normal ovary for both borderline (P = 0.02) and malignant groups (P = 0.01). Tumour cell staining with the bcl-2 antibody was significantly reduced when tumour mass had to be left behind compared with those with no visible remaining tumour (P = 0.03 and 0.003 for weakly and strongly stained tumours respectively). The expression of bcl-2 in malignant tumour cells was inversely correlated with the expression of p53. Bcl-2 expression was correlated with survival with significantly reduced survival in weakly (P = 0.02) and unstained (P < 0.001) groups compared with those patients having strongly stained malignant tumour cells. This correlation between the presence of bcl-2 and survival was maintained in the subgroups of patients with advanced disease or with residual tumour bulk and was also the case in patients having p53-positive tumours. Our results indicate an inhibitory role of bcl-2 in development and progression of ovarian tumours.
Br J Cancer 1995 Nov
PMID:Expression and prognostic significance of Bcl-2 in ovarian tumours. 757 91

Apoptosis is a major form of cell death induced by chemotherapeutic drugs. Overexpression of the proto-oncogene bcl-2 can prevent apoptosis in various types of cells. We have constructed a HeLa S3 cell line in which the expression of bcl-2 can be controlled by the concentration of tetracycline in the medium. Using this system, we show that apoptosis induced by various cytostatic treatments could be delayed by the overexpression of bcl-2, as assayed by vital dye exclusion, apoptotic nuclei morphology, DNA histogram shift, and DNA fragmentation. Quantitative analysis revealed a hyperbolic curve when protection from apoptosis was plotted against the amount of Bcl-2. When cells were treated with aphidicolin for 12, 24, or 36 h and then replated in fresh media to assay for colony formation, the majority of cells that did not show apoptotic morphology at the time of drug removal failed to form colonies. Furthermore, Bcl-2 did not increase colony formation after 12-36 h of aphidicolin treatment. Therefore, with aphidicolin treatment, cells were committed to the death program upstream of the point of Bcl-2 action.
Cancer Res 1995 Nov 01
PMID:BCL-2 expression delays drug-induced apoptosis but does not increase clonogenic survival after drug treatment in HeLa cells. 758 31

Using a highly tumorigenic human breast cancer model (Ha-ras-transfected MCF7 cell line) we analyzed the efficacy of the differentiation-inducing agent sodium phenylacetate (NaPA), both in vitro and in vivo. NaPA-treated MCF7ras cells showed dose-dependent growth inhibition from 2.5 to 15 mM without apparent toxicity. Western blot analysis showed a Bcl-2 down-regulation after 48 h treatment with 5 mM NaPA, together with apparition of apoptotic nuclei by DAPI staining. Mice bearing MCF7ras xenografts (n = 40) were treated for 2 weeks through s.c.-delivering osmotic pumps, followed by 6 weeks of daily i.p. NaPA administration. After 3 weeks, the treated tumors showed growth arrest without regression for the whole observation time, e.g., 12 weeks. Immunohistochemical analysis showed Bcl-2 down-regulation and differentiation patterns: decrease of Ki-67 and increase of steroid receptors (estrogen and progesterone receptors) compared to controls. Cells cultured from treated tumors (II.b) displayed pseudotrabecular disposition as MCF7ras cells treated in vitro. They also showed a higher NaPA sensitivity, together with 70% Bcl-2 down-regulation as compared to the derived cells of untreated tumors (II.a). When reinjected into nude mice, II.b cells induced only one poorly vascularized, noninvasive tumor (8%) with lower proliferation index, 100% progesterone receptor positive cells, and 35% terminal deoxynucleotidyltransferase-mediated dUTP-X nick end labeling (+) nuclei, as compared to 100% induction of highly vascularized and invasive tumors with 3% terminal deoxynucleotidyltransferase-mediated dUTP-X nick end labeling (+) nuclei induced by II.a cells.
Cancer Res 1995 Nov 15
PMID:Sodium phenylacetate induces growth inhibition and Bcl-2 down-regulation and apoptosis in MCF7ras cells in vitro and in nude mice. 758 64

The expression of the Bcl-2 oncoprotein was studied in pre-treatment bone-marrow samples from 63 patients with multiple myeloma, using an immunohistochemistry technique. A variable expression of the Bcl-2 protein was found in myeloma cells. 43% of the patients had strong expression of the Bcl-2 protein in the malignant cells. Forty patients received alpha-interferon, whereas 23 patients received melphalan/prednisone therapy. A significant association (p = 0.012) was found between high levels of Bcl-2 expression in myeloma cells and resistance to interferon therapy. No such correlation was found in the melphalan/prednisone treated patients. The data indicate that over-expression of Bcl-2 may be a cause for resistance to interferon therapy in myeloma and that staining for Bcl-2 expression in myeloma cells may have a predictive value for this treatment.
Int J Cancer 1995 Oct 09
PMID:Response to interferon therapy in patients with multiple myeloma correlates with expression of the Bcl-2 oncoprotein. 759 Dec 2


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