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 multidisciplinary approach was taken to investigate the intracellular locations of the 26-kDa integral membrane protein encoded by the bcl-2 gene. Subcellular fractionation analysis of a t(14;18)-containing lymphoma cell line revealed the presence of Bcl-2 protein in nuclear, heavy-membrane, and light-membrane fractions but not in cytosol. Sedimentation of heavy-membrane fractions in Nycodenz and Percoll continuous gradients demonstrated comigration of p26-Bcl-2 with mitochondrial but not other organelle-associated proteins. Fractionation of light-membrane fractions using discontinuous sucrose-gradients revealed association of Bcl-2 protein primarily with lighter-density microsomes (smooth endoplasmic reticulum) as opposed to heavy-density microsomes (rough endoplasmic reticulum). Immune microscopy studies using laser-scanning microscopy, pre- and postembedding electron microscopic methods, and six different anti-Bcl-2 antibodies demonstrated Bcl-2 immunoreactivity in the nuclear envelope and outer mitochondrial membrane in a patchy distribution. Furthermore, anti-Bcl-2 antibody immunoreactivity generally appeared to directly overlie the nuclear envelope in high magnification electron microscopic studies, reminiscent of nuclear pore complexes. Addition of in vitro translated p26-Bcl-2 to isolated translocation-competent mitochondria revealed transmembrane domain-dependent association of Bcl-2 protein with mitochondria but provided no evidence for import into a protease-resistant compartment, consistent with immunomicroscopic localization to the outer mitochondrial membrane. Taken together, the findings demonstrate that p26-Bcl-2 resides primarily in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membrane in a nonuniform distribution suggestive of participation in protein complexes perhaps involved in some aspect of transport.
Cancer Res 1993 Oct 01
PMID:Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. 840 48

When established in culture, human neuroblastoma cell lines typically are comprised of heterogeneous cellular subpopulations, including neuroblastic (N-type), substrate-adherent (S-type), and intermediate (I-type) cells that can be distinguished by their characteristic morphologies and expression of differentiation-associated antigens. Here we examined the relative levels of the Bcl-2 oncoprotein in 15 clones derived from four different neuroblastoma cell lines. Among six clones isolated from the SK-N-SH line, levels of p26-Bcl-2 correlated with morphology and differentiation markers with the hierarchy of bcl-2 expression being: N-type cells > N/I-type > I-type > S-type. Furthermore, stimulation of one of the N-type clones, SH-SY5Y, with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, induced differentiation toward a more neuronal-like phenotype and resulted in a 5- to 10-fold elevation in the relative levels of Bcl-2 protein. High relative amounts of p26-Bcl-2 protein were also found in an N-type clone derived from the SMS-KCN line. In two N-type clones derived from the LA-N-1 line, however, levels of Bcl-2 protein were only moderately elevated, and in one N-type clone from the SK-N-BE(2) line the levels of Bcl-2 protein were low. Thus, high relative levels of Bcl-2 oncoprotein are not a universal feature of N-type cells (three of six clones tested). In contrast, all 5 of the S-type clones evaluated contained relatively low levels of Bcl-2 protein, suggesting that these cells (which may represent embryonic precursors of Schwann, glial, and melanocytic cells) do not typically express the bcl-2 gene at high levels. Consistent with this inverse correlation between Bcl-2 protein levels and S-type characteristics, stimulation of an I-type clone derived from the SK-N-BE(2) line with 5-bromodeoxyuridine was accompanied by an accumulation of S-type cells in these cultures, decreased Bcl-2 protein, diminutions in the neuronal markers neurofilament-M and neuron-specific enolase, and an increase in the relative levels of the S-type marker proteins vimentin and beta-2-microglobulin. Conversely, stimulation of this I-type clone with retinoic acid resulted in an accumulation of N-type cells (which are thought to represent embryonic precursors of sympathetic neurons), decreased vimentin and beta-2-microglobulin, increased neurofilament-M, and a marked elevation in p26-Bcl-2.(ABSTRACT TRUNCATED AT 400 WORDS)
Cancer Res 1993 Oct 15
PMID:Regulation of Bcl-2 oncoprotein levels with differentiation of human neuroblastoma cells. 840 88

The uniformly fatal plasma cell malignancy, multiple myeloma (MM), currently represents 10-15% of hematologic neoplasms in the USA and has been steadily increasing in incidence for several decades. Therapeutic alternatives have lagged significantly behind insights into the biology and pathogenesis of this entity. Traditionally felt to be a neoplasm of fully differentiated plasma cells, evidence has been mounting that the self renewing population consist of cells derived from a much earlier compartment; perhaps prior to B-cell lineage commitment or even at the level of an earlier 'stem cell'. Bcl-2 protein overexpression has been almost uniformly seen in both clinical myeloma specimens as well as in myeloma cell lines. The failure to consistently identify the t(14;18) translocation, normally found in follicular lymphomas and characteristically associated with overexpression of bcl-2, implies a unique mechanism in MM. A number of cytokines, including TNF alpha, IL-1 and IL-6 have been found to play a central role not only in the biology of the malignant clone but also in the bony and other systemic manifestations of this disease. Since both IL-6 and bcl-2 protein have been shown to prevent programmed cell death, this may be the unifying event in MM. Standard therapy for MM has been an alkylating agent and corticosteroid. Combination chemotherapy provides more prompt palliation but no clear survival advantage. In advanced stages, adriamycin may offer some survival advantage. High dose chemotherapy with or without stem cell support offers a potentially curative therapeutic approach. New interventions directed at the complex cytokine networks pertinent to the pathogenesis of MM are an exciting new area of investigation. Identification of new prognostic parameters as well as new active agents remains the central theme in clinical myeloma research.
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PMID:Biology and treatment of multiple myeloma. 846 29

Bcl-2 is a novel protooncogene which prolongs cell survival and suppresses apoptosis. We examined whether constitutive expression of transfected human bcl-2 conferred resistance to two different DNA damaging drugs, nitrogen mustard (HN2) and camptothecin (CPT) in a murine, IL-3 dependent cell line (FL5.12). HN2 treatment produced 2-fold less cell death and DNA degradation in cells overexpressing bcl-2 relative to control cells transfected with a construct bearing only the neoR gene. DNA degradation was characterized by oligonucleosomal length fragments indicating that programmed cell death or apoptosis had occurred. Equimolar HN2 produced similar extents of interstrand cross-link formation and repair in each cell line. Cell cycle characteristics were similar for both cell lines following equimolar HN2 treatment, exhibiting a brief S phase delay followed by a longer G2 arrest. Time course studies indicated that DNA fragmentation occurred following peak G2 arrest in control cells and 12 h later in bcl-2 transfected cells. Equimolar CPT exposure also induced 2-fold less death and apoptotic DNA fragmentation in bcl-2 transfected compared to control cells. DNA single strand break formation and resealing kinetics were comparable in both cell lines following equimolar CPT treatment. CPT caused similar cell cycle perturbations in both cell lines, with a brief S phase block detectable 12 h after an equimolar drug dose. Kinetic studies showed apoptosis occurred following maximal S phase arrest in control and 12 h later in bcl-2 transfected cells. By contrast, IL-3 withdrawal produced rapid and extensive DNA degradation and apoptosis in controls 24 h postwithdrawal, and this process was inhibited 3-4-fold in bcl-2 transfectants. Cell cycle analysis showed both cell lines arrested in G0/G1 following IL-3 removal. In summary, bcl-2 transfection affords a 2-fold protection from HN2 and CPT cytotoxicity and decreases drug induced apoptosis in FL5.12 cells, despite the different mechanisms of action and cell cycle effects of each agent. Bcl-2 overexpression appears to represent a novel drug resistance mechanism of potential clinical significance.
Cancer Res 1993 Apr 15
PMID:Constitutive expression of human Bcl-2 modulates nitrogen mustard and camptothecin induced apoptosis. 846 5

Dysplasia in squamous metaplasia of the respiratory tract was believed to be a reversible premalignant lesion. Recently, presumably irreversible genetic alterations have been demonstrated in squamous metaplasia with dysplasia in lung-resection specimens. The genetic alterations were closely similar to those in adjacent bronchial carcinoma. There remains the question of which changes in squamous metaplastic lesions are premalignant, and which of these changes predict the occurrence of carcinoma of the respiratory tract. The purpose of this study was to determine the positive predictive value for respiratory-tract malignancy of the grade of dysplasia, p53 immunoreactivity, proliferative activity, and Bcl-2 in bronchial biopsy specimens exhibiting squamous metaplasia. Bronchial biopsies of 51 patients with squamous metaplasia diagnosed between 1982 and 1993 were used. Immunohistochemistry was done after microwave pretreatment of the biopsy specimens. Only unequivocally stained nuclei were counted. Normal bronchial epithelium obtained from autopsies was used as a control. In 31 patients, a synchronous or metachronous carcinoma was present (61%). Positive p53 immunoreactivity was found in 22 of the 51 patients (43%). The positive predictive values of p53 and of a high grade of dysplasia for carcinoma of the respiratory tract were 91% and 80%, respectively. Although the hyperproliferative state of squamous metaplastic lesions was clearly established, neither the percentage of MIB-1 labelling nor the mitotic index distinguished patient groups with and without carcinoma. No increased Bcl-2 immunostaining was found in squamous metaplasia. In conclusion, p53 immunoreactivity in squamous metaplastic lesions in bronchial biopsies is a marker of carcinoma of the respiratory tract.
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PMID:P53 in squamous metaplasia: a marker for risk of respiratory tract carcinoma. 854 51

Normal peripheral blood B lymphocytes undergo spontaneous apoptosis in vitro, and this process is regulated positively and negatively by several immunomodulatory stimuli. We have shown previously that Bcl-2 protein levels are unaltered by these factors, suggesting a Bcl-2-independent regulation of apoptosis in this system. Here, we have investigated the possibility that the three recently identified Bcl-2 homologues, Bax, Bcl-x, and Mcl-1, could be involved instead. Freshly isolated cells expressed both Bax and Mcl-1 protein, but only low levels of Bcl-xL and no detectable Bcl-xS, as determined by Western blot analysis. Upon culture of cells with apoptotic or survival stimuli, Bax and Bcl-xL protein levels remained relatively unchanged. By contrast, Mcl-1 levels decreased markedly in cells undergoing apoptosis in medium and, even more dramatically, after treatment with the apoptotic stimuli transforming growth factor beta 1 and forskolin. This decrease was rapid and preceded cell death. Furthermore, all the survival stimuli tested (interleukin 4, anti-IgM antibodies, and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate) prevented the decline in Mcl-1 levels. This striking correlation between cell survival and Mcl-1 expression in peripheral blood B cells suggests the possible involvement of Mcl-1, instead of Bcl-2, in the regulation of apoptosis in these cells. The present study is the first one linking this novel Bcl-2 homologue to the control of cell death in normal cells.
Cancer Res 1996 Jan 01
PMID:Expression of the Bcl-2 homologue Mcl-1 correlates with survival of peripheral blood B lymphocytes. 854 71

Toremifene exerts multiple and varied effects on the gene expression of human peripheral mononuclear cells. After short-term, in vitro exposure to therapeutical levels, distinct changes in P-glycoprotein, steroid receptors, p53 and Bcl-2 expression take place. In view of the increasing use of antiestrogens in cancer therapy and prevention, there is obvious merit in long-term in vivo studies to be conducted.
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PMID:The effect of Toremifene on the expression of some genes in human mononuclear cells. 856 86

The expression of Bcl-2 protein in 29 small cell carcinomas (SCCs; 6 surgical and 15 biopsy specimens obtained from various organs, 7 metastatic lymph nodes, and 1 metastatic liver tissue) was investigated by immunohistochemical technique. Negative staining was observed in only two cases (7%). The majority of Bcl-2-positive tumors had > 95% positive cells, with a moderate staining intensity. A combined small-cell lung cancer showed discordant staining results between two different histology types. No correlations of Bcl-2 immunoreactivity with p53 expression and clinical staging were found. Our findings suggest that Bcl-2 expression may play a certain role in the early phases of SCC tumorigenesis, or that it may solely be a succeeding property directly derived from the tumor progenitor cells. As the Bcl-2 protein was present in most cases, it is not a useful prognostic or treatment marker for the cancer.
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PMID:Immunohistochemical detection of Bcl-2 protein in small cell carcinomas. 857 Jan 34

Knowledge about the mechanisms that regulate the expression of the family of BCL-2 genes and the biochemical characteristics of their encoded proteins is beginning to provide new insights into the origins of cancer and our all too often inability to adequately treat it. With better understanding of the functional significance of these protein-protein interactions involving Bcl-2, Bax, and other members of the Bcl-2 protein family and with insights into the structural details of these interactions, it may eventually be possible to develop novel pharmacological agents that improve tumor responses to currently available anticancer drugs and that have other clinically relevant uses as well.
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PMID:Bcl-2 family proteins: regulators of chemoresistance in cancer. 859 45

Human promyelocytic leukemia HL-60 cells treated with 8-chloroadenosine-3',5'-cyclic monophosphate (8-Cl-cAMP) undergo growth arrest and subsequently die by apoptosis. We describe here the isolation of a variant of HL-60 cells, HCW-2, which was resistant to the cytotoxic effects of 8-Cl-cAMP, but still underwent growth arrest. Thus, HCW-2 cells appeared to be altered in their ability to undergo apoptosis. HCW-2 cells were also completely refractory to the apoptotic action of cycloheximide and staurosporine, two compounds which were very potent inducers of apoptosis in the parental HL-60 cells, suggesting that the resistance to apoptosis was not unique to 8-Cl-cAMP. Western blot analysis demonstrated that the parental HL-60 cells expressed both Bcl-2 and Bax, two factors known to be intimately involved in the control of apoptosis. Surprisingly, HCW-2 cells no longer expressed Bcl-2 protein and paradoxically contained Bax protein at a level that was approximately 50-fold higher than in HL-60 cells. However, Northern and Western analyses indicated that the apoptotic suppressor gene, bcl-xL, which is not expressed in the parental HL-60 cells, was expressed in HCW-2 cells. Thus, the Bcl-2-independent resistance of HCW-2 cells to apoptotic induction is discussed in terms of the expression of bcl-xL.
Cancer Res 1996 Apr 01
PMID:Isolation and characterization of an apoptosis-resistant variant of human leukemia HL-60 cells that has switched expression from Bcl-2 to Bcl-xL. 860 11


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