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)

We report overexpression of the proto-oncogene bcl-2 in gastrointestinal adenocarcinoma and its precursor lesions. The bcl-2 proto-oncogene is centrally involved in the oncogenesis of human follicular lymphoma via a chromosomal translocation t(14;18)(q32;q21) and is also expressed in the epithelial regenerative compartment or the basal crypts of the normal colon and small intestine. We describe an immunohistochemical analysis of fixed, paraffin-embedded tissue using both a polyclonal rabbit and a monoclonal mouse antibody to the Bcl-2 protein. In addition to confirming bcl-2 expression in normal colonic and small intestinal crypts, we also observed expression in the gastric epithelial regenerative compartment, the mucous neck region. No increased expression was found in nonneoplastic or inflammatory gastrointestinal conditions, including ulcerative colitis, Crohn's disease, or inflammatory or hamartomatous polyps. Increased bcl-2 expression, however, was present in hyperplastic colonic polyps and in the majority of dysplastic lesions, from the earliest precursors through large adenomas, high grade flat dysplasia, and adenocarcinoma, all in comparison with adjacent internal control normal epithelium. Increased expression was present in dysplastic glandular lesions from all gastrointestinal sites, including colon, small bowel, and stomach. Furthermore, bcl-2 expression was frequently abnormal in nondysplastic epithelium surrounding dysplastic lesions, suggesting that altered expression occurred before the development of morphological dysplasia. Specifically, directly contiguous morphologically nondysplastic epithelium often showed abnormal bcl-2 expression throughout the full length of the crypt-villus axis. This expression pattern gradually diminished to involve only the crypt base (the normal pattern of expression), proceeding away from malignant or dysplastic lesions. Abnormal bcl-2 immunoreactivity in 1), the earliest precursor dysplastic lesions and its persistence throughout neoplastic progression and 2), contiguous morphologically unaltered nondysplastic epithelium suggests that bcl-2 alterations occur early during the morphological and molecular sequence of events leading to gastrointestinal epithelial neoplasia.
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PMID:The bcl-2 proto-oncogene and the gastrointestinal epithelial tumor progression model. 785 28

The Caenorhabditis elegans gene ced-9 and the human proto-oncogene bcl-2, both of which protect cells from programmed cell death, are members of the same gene family. ced-9 and bcl-2 were discovered because of the effects of dominant gain-of-function mutations. Such bcl-2 mutations, which are commonly found in follicular lymphoma, are translocations that result in over-expression of a normal Bcl-2 protein in B cells. Here we report that, by contrast, the ced-9(n1950) gain-of-function mutation affects the open reading frame of ced-9 and results in a glycine-to-glutamate substitution in a region highly conserved among all ced-9/bcl-2 family members. We conclude that this glycine has an important function in ced-9 regulation, and we suggest that alteration of this glycine in other members of the ced-9/bcl-2 family might lead to oncogenic activation. We also present genetic evidence suggesting that the CED-9 protein might exist in two distinct forms that have opposite effects on cell death.
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PMID:Activation of C. elegans cell death protein CED-9 by an amino-acid substitution in a domain conserved in Bcl-2. 818 60

A polymerase chain reaction analysis of biopsy specimens from a total of 52 patients with Hodgkin's disease has revealed the presence of the t(14;18) chromosomal translocation in 14 cases (28%). Twelve involved the major breakpoint region and two included the minor cluster region of the bcl-2 gene. Direct sequencing of the amplified 14q+ junctions from the initial four positive cases (from 21 biopsies) has been previously published and demonstrated the similarity in nature of the break-points to those described in follicular lymphoma and lymphoid hyperplasia. The 52 biopsies have also been studied with a monoclonal antibody to immunolocalize the Bcl-2 protein. In all cases Bcl-2 positivity was observed in the majority of surrounding lymphocytes. However, in 11 cases, positive immunostaining in the Sternberg-Reed cells was also observed. Three of these cases contained the t(14;18) translocation, but 11 cases which were positive for the t(14;18) by PCR did not show Bcl-2 protein staining in the Sternberg-Reed cells. This data confirms the presence of t(14;18) in 28% of biopsies from Hodgkin's disease and demonstrates Bcl-2 protein staining in a variable proportion of Sternberg-Reed cells of some cases.
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PMID:The t(14;18) chromosomal translocation and Bcl-2 protein expression in Hodgkin's disease. 805 70

Bcl-2 is a proto-oncogene initially described in the (14;18) translocation in follicular lymphoma. It has been shown to prolong cell survival by preventing apoptosis. Endometrium undergoes rapid proliferation and differentiation under hormone control and is thus an excellent model to study the hormone dependency of Bcl-2 expression. We studied Bcl-2 expression by an immunohistochemical method in 53 samples of normal endometrium randomly distributed throughout the menstrual cycle, as well as five samples of hyperplastic endometrium. Bcl-2 staining predominated in glandular cells and peaked at the end of the follicular phase. Bcl-2 expression disappeared at the onset of secretory activity. The stroma, surface lining epithelium and arterial vessels also displayed cyclic variations in Bcl-2 expression. These results strongly suggest hormone-dependent regulation of Bcl-2 expression, which could play an important role in tumorigenesis.
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PMID:Bcl-2 expression in normal endometrium during the menstrual cycle. 820 60

The t(14;18) chromosomal translocation occurs in most follicular non-Hodgkin's lymphomas and places the Bcl-2 gene on chromosome 18q21 into the immunoglobulin JH region on chromosome 14q32. This translocation can be exploited to detect clonal malignant cells bearing this genetic alteration. A polymerase chain reaction (PCR) assay amplifying over the major breakpoint region (mbr) and minor cluster region (mcr) was developed and optimized. In this report, the sensitivity and reproducibility of this semiquantitative assay, performed on a relatively large number of clinical samples is shown. A titration curve of DNA made from a t(14;18)- cell line admixed with increasing ratios of a t(14;18)+ cell line was used to demonstrate that one t(14;18)+ cell in 100,000 t(14;18)- cells could reproducibly be detected. Occult lymphoma cells, not detected by standard morphologic analysis, were demonstrated in almost two-thirds of the bone marrow and peripheral blood specimens obtained from untreated patients with follicular lymphoma. Of 11 bone marrow samples assessed, seven were positive for occult disease by PCR amplification over the mbr and one was positive over the mcr. Of these six positive marrow samples, only three had been reported positive by standard morphologic criteria. In addition, seven of nine peripheral blood samples assessed were positive over the mbr and one additional sample was positive over the mcr. None of these were morphologically positive. Seven of the above patients would have been upstaged if these results were utilized for staging, including two of three patients with stage I or stage II disease. PCR-detectable occult disease persisted in four of four patients assessed both pre- and post-treatment, even after aggressive multi-drug combination chemotherapy in two of these patients. The clinical significance of detecting this occult disease must await the study of larger numbers of patients and the clinical outcomes of patients with occult disease and patients without occult disease.
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PMID:Sensitive and reproducible detection of occult disease in patients with follicular lymphoma by PCR amplification of t(14;18) both pre- and post-treatment. 841 70

The bcl-2 gene is rearranged in most cases of follicular lymphoma and the breakpoint clusters into two specific regions: mbr and mcr. Rearrangements to immunoglobulin heavy chain genes (IgH) result in a deregulation of the gene and increased transcription of mRNA for the bcl-2 protein. In chronic lymphocytic leukaemia (CLL) expression of bcl-2 protein is increased but rearrangement of the gene can be found only in a minority of cases: commonly a variant translocation with a breakpoint region located 5' of the bcl-2 gene (vcr) with preferential rearrangement to immunoglobulin light chain genes. We have analysed breakpoints in mbr and vcr in malignant cells from 96 patients with B-CLL, 45 with hairy cell leukaemia (HCL) and 41 with high- and low-grade non-Hodgkin's lymphomas (NHL). Vcr rearrangements were observed in nine patients (12%) with B-CLL. Four patients had co-migration of rearranged bcl-2 bands to kappa genes and two patients to IgH. Cytogenetic abnormalities involving 18q21, the site of the bcl-2 gene, was found in two cases only. In several cases with bcl-2 gene rearrangement chromosomal aberrations not including 18q21 were observed. In six patients (two B-CLL, one follicular lymphoma, one immunocytoma and two high-grade lymphomas), breakpoints in both vcr and mbr were found. In HCL a rearrangement in the vcr region was found in one case. Bcl-2 protein immunostaining of B-CLL showed intense bcl-2 expression in all cases and no correlation was found between gene rearrangement and protein expression. Our study confirms that breakpoints in the bcl-2 gene commonly cluster to the vcr region in B-CLL, but in most cases over-expression of bcl-2 protein has to be explained by other mechanisms than bcl-2 gene rearrangement. We also report that simultaneous breakpoints in mbr and vcr is a recurrent phenomenon in B-CLL and in other high- and low-grade non-Hodgkin's lymphomas.
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PMID:Bcl-2 rearrangements with breakpoints in both vcr and mbr in non-Hodgkin's lymphomas and chronic lymphocytic leukaemia. 861 30

The prototypic mammalian regulator of cell death is bcl-2, the oncogene implicated in the development of human follicular lymphoma. Several homologues of bcl-2 are now known. Using a PCR-based strategy we cloned a novel member of this gene family, denoted bcl-w. The gene, which is highly conserved between mouse and human, resides near the T-cell antigen receptor alpha gene within the central portion of mouse chromosome 14 and on human chromosome 14 at band q11. Enforced expression of bcl-w rendered lymphoid and myeloid cells refractory to several (but not all) cytotoxic conditions. Thus, like Bcl-2 and Bcl-x, the Bcl-w protein promotes cell survival, in contrast to other close homologues, Bax and Bak, which facilitate cell death. Comparison of the expected amino acid sequence of Bcl-w with that of these relatives helps to delineate residues likely to convey survival or anti-survival function. While expression of bcl-w was uncommon in B or T lymphoid cell lines, the mRNA was observed in almost all murine myeloid cell lines analysed and in a wide range of tissues. These findings suggest that bcl-w participates in the control of apoptosis in multiple cell types. Its functional similarity to bcl-2 also makes it an attractive candidate proto-oncogene.
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PMID:bcl-w, a novel member of the bcl-2 family, promotes cell survival. 876 Dec 87

To evaluate CD34+ selection of peripheral blood stem cells (PBSC) as a graft for autologous transplantation. Eight relapsing follicular lymphoma (FL) patients were submitted to CD34+ autologous stem cell transplantation (ASCT). All patients received at least two front line conventional therapies; mean time to treatment failure (TTF) was 4.5 months. Patients had disseminated stage III-IV disease after a median number of 2.1 relapses. Chemotherapy and G-CSF were used as mobilization for leukapheresis. CEPRATE SC concentrator (CellPro, Inc, Bothell, WA) was used to select CD34+ cells from leukapheresis products. With a mean of 1.8 leukaphereses per patient, 8.1 x 10(8) mononuclear cells (MNCs)/kg were collected. After the selection process, the median number of MNCs was 9.4 x 10(6)/kg; 4.3 x 10(6)/kg CD34+ cells and 17 x 10(4)/kg CFU-GM, with a purity of 83.7% and a viability of 89.2%. Mbr bcl2/IgH PCR analysis of 5 grafts showed that initial buffy-coat, and CD34- fractions were negative in 3 cases and positive in 2 cases (from whom selected CD34+ fraction remained positive in 1 case). After a conditioning regimen including total body irradiation, cyclophosphamide and etoposide, CD34+ selected cells were reinfused. All patients but one had successful engraftment, median time to WBC > 1 x 10(9)/l was 12 days and platelets > 50 x 10(9)/l 17 days. No severe infectious complications were seen. After transplant, with a minimum follow up of 2 years, 5 patients are still in complete remission (CR). Three patients have relapsed after 1 year of transplant with a mean TTF of 15.6 months. We conclude that PBSC CD34+ selection for ASCT was a safe technique, capable of reconstituting hemopoiesis without severe complications for high risk FL patients included in this study. The effects of tumor cell purging need to be evaluated in a larger series.
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PMID:Peripheral blood stem cell CD34+ autologous transplant in relapsed follicular lymphoma. 908 36

The roles of Bcl-2 protein and the protein ratio of Bcl-2/Bax in regulating cell growth in various lymphoma cell lines were examined. A dose-dependent decrease in Bcl-2 protein expression was observed in the different lymphomas incubated with lipid-incorporated bcl-2 antisense oligonucleotides (L-bcl-2). Growth inhibition was observed in a transformed follicular lymphoma (FL) cell line, which has the t(14;18) translocation and Bcl-2 protein overexpression. One of the mechanisms by which L-bcl-2 growth inhibition is mediated in these transformed FL cells might be through apoptotic induction, because the treated cells had an increased apoptotic index and showed the typical DNA fragmentation. These studies indicate that Bcl-2 protein is critical in the growth regulation of transformed FL cells. L-bcl-2 did not induce growth inhibition in lymphoma cells not expressing Bcl-2 or Bax protein. Thus, the protein ratio of Bcl-2/Bax may also be important in regulating the growth of these lymphomas.
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PMID:Apoptotic induction in transformed follicular lymphoma cells by Bcl-2 downregulation. 971 67

Cross-linking of B cell antigen receptor (sIg) elicits different biological responses, including cell activation, proliferation, differentiation, anergy and cell death depending on the maturational stage of the cell. We established the tumor cell lines HF-1.3.4 and HF-4-9 from two patients with follicular lymphoma. Both cell lines carry the characteristic t(14;18) chromosomal translocation and display constitutively overexpressed Bcl-2. HF-1.3.4 represents a mature B cell with sIgG and several somatic hypermutations in its Ig genes, while HF-4-9 is a less mature B cell, expressing sIgM and only a few mutations in its Ig genes. Cross-linking of sIg with antibodies leads to apoptosis in HF-1.3.4 cells but not in HF-4-9 cells. Triggering of sIg induced, within seconds, identical tyrosine phosphorylation of p53/56lyn protein tyrosine kinase (PTK) and p55blk PTK in both of the cell lines; however, a prominent tyrosine phosphorylation and activation of p72syk PTK only in HF-1.3.4 cells. We conclude that p72syk PTK is of importance in relaying apoptotic signalling upon sIg cross-linking in the HF-1.3.4 cell line. Given the mature phenotype of the HF-1.3.4 cell line it serves as a model for the late negative selection during B cell ontogeny. Moreover, our results question the current concept that a constitutive overexpression of BcI-2 confers resistance to sIg ligation-induced apoptosis in lymphoma cells.
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PMID:p72syk protein tyrosine kinase: an early transducer of sIgG-triggered apoptotic signalling in human follicular lymphoma cells. 979 24


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