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 maintenance of homeostasis in normal tissues reflects a balance between cell proliferation and cell death. The importance of both positive and negative regulators of cell growth has been well documented in neoplasia. Bcl-2 argues for the existence of a new category of oncogenes, regulators of cell death. The bcl-2 gene was identified at the chromosomal breakpoint of t(14; 18) bearing B cell lymphomas. Bcl-2 has proved to be unique among protooncogenes in blocking programmed cell death rather than promoting proliferation. In adults, bcl-2 is topographically restricted to progenitor cells and longlived cells but is much more widespread in the developing embryo. Transgenic mice that overexpress bcl-2 in the B cell lineage demonstrate extended cell survival, and progress to high grade lymphomas. Bcl-2 has been localized to mitochondria, endoplasmic reticulum and nuclear membranes, also the sites of reactive oxygen species generation. Bcl-2 does not appear to influence the generation of oxygen free radicals but does prevent oxidative damage to cellular constituents including lipid membranes. Bcl-2 deficient mice complete embryonic development and display relatively normal haematopoietic differentiation but undergo fulminant lymphoid apoptosis of thymus and spleen. Moreover, they demonstrate two potentially oxidation related pathologies: polycystic kidney disease and hair hypopigmentation. A family of bcl-2 related genes is emerging that includes Bax, a conserved homolog that heterodimerizes in vivo with bcl-2. A pre-set ratio of Bcl-2/Bax appears to determine the survival or death of cells following an apoptotic stimulus.
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PMID:Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. 814 17

B cell chronic lymphocytic leukemia (B-CLL) represents the most frequent adult leukemia in the Western world. The molecular pathogenesis of B-CLL is largely unknown. Although initial reports on small panels of cases had suggested a role for Bcl-1 and Bcl-2 oncogene activation in B-CLL, later investigations failed to confirm these data. Among tumor suppressor genes, p53 mutations have been reported in a fraction of cases. In this study, we have attempted a conclusive definition of the involvement of dominantly acting oncogenes (Bcl-1 and Bcl-2) and tumor suppressor loci (p53, 6q-) in 100 cases of B-CLL selected for their CD5 positivity and Rai's stage (0 to IV). Rearrangements of Bcl-1 and Bcl-2 and deletions of 6q and 17p were analyzed by Southern blot using multiple probes. Mutational analysis (single strand conformation polymorphism and polymerase chain reaction direct sequencing) was used to assay p53 inactivation. No alterations of Bcl-1 or Bcl-2 were detected in the 100 cases tested. Mutations of p53 were found in 10/100 cases without any significant association with clinical stage. Deletions of 6q were present in 4/100 cases. Overall, our data indicate that: 1) contrary to previous reports, Bcl-1 and Bcl-2 rearrangements are not involved in CD5+ B-CLL pathogenesis and 2) p53 mutations are present in 10% of cases at all stages of the disease.
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PMID:Analysis of alterations of oncogenes and tumor suppressor genes in chronic lymphocytic leukemia. 820 69

bcl-2 is the first member of a new class of protooncogenes the products of which inhibit programmed cell death (PCD) or apoptosis. We have previously determined that Bcl-2 is expressed in a significant percentage of untreated primary neuroblastoma (NBL) tumors. In these specimens Bcl-2 expression correlated with other markers of poor prognosis suggesting a role for Bcl-2 in the malignant behavior of NBL tumor cells. To investigate this possibility, a Bcl-2-negative human NBL cell line (Shep-1) was transfected with a bcl-2 expression vector (pSFFVneo-bcl-2). Multiple unique clones were isolated which showed variable levels of Bcl-2 protein by quantitative immunoprecipitation. Vector-transfected controls were generated simultaneously. Clones expressing high levels of Bcl-2 were resistant to cisplatin- and etoposide-induced cytotoxicity in a dose-dependent manner. Analysis of propidium iodide-stained nuclei by flow cytometry after cisplatin or etoposide treatment revealed marked DNA degradation in vector-transfected controls whereas bcl-2 transfectants showed a dose-dependent inhibition of DNA degradation. Analysis by pulsed-field gel electrophoresis revealed relatively large fragment DNA degradation (approximately 50 kilobases) in the absence of internucleosomal degradation in vector-transfected control cells treated with either cisplatin or etoposide. In contrast, Bcl-2-expressing cells showed significantly less DNA degradation at all time points. These single gene transfection experiments have revealed that expression of Bcl-2 renders specific NBL cells resistant to chemotherapy-induced PCD and support the hypothesis that Bcl-2 enhances the malignant phenotype of NBL by promoting tumor resistance to chemotherapy agents.
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PMID:Bcl-2 inhibits chemotherapy-induced apoptosis in neuroblastoma. 820 48

Transformation of primary rodent cells by the adenovirus E1A and E1B oncogenes is a two-step process, where E1A-dependent induction of proliferation is coupled to E1B-dependent suppression of programmed cell death (apoptosis). The E1B gene encodes two distinct transforming proteins, the 19K and 55K proteins, both of which independently cooperate with E1A. E1B 19K or 55K protein, or the human Bcl-2 protein, functions to suppress apoptosis and thereby permits transformation with E1A. The E1B 55K protein blocks p53 tumor suppressor protein function, indicating that p53 may mediate apoptosis by E1A. In the mutant conformation, p53 blocked induction of apoptosis by E1A and efficiently cooperated with E1A to transform primary cells. When p53 was returned to the wild-type conformation, E1A+p53 transformants underwent cell death by apoptosis. This induction of apoptosis by conformational shift of p53 from the mutant to the wild-type form was inhibited by expression of the E1B 19K protein. Thus, the p53 protein may function as a tumor suppressor by initiating a cell suicide response to deregulation of growth control by E1A. E1B 19K and 55K proteins provide separate mechanisms that disable the cell suicide pathway of p53.
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PMID:Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. 838 80

The product of the c-myc proto-oncogene is an important positive regulator of cell growth and proliferation. Recently, c-Myc has also been demonstrated to be a potent inducer of apoptosis when expressed in the absence of serum or growth factors. To further examine Myc-induced apoptosis, we coexpressed the proto-oncogene bcl2, which has been shown to block apoptosis in other systems, with c-myc in serum-deprived Rat 1a fibroblasts. Here we report that ectopic expression of bcl2 specifically blocks apoptosis induced by constitutive c-myc expression. Constitutive c-myc expression in serum-deprived Rat 1a cells caused a > 15-fold increase in the number of dead cells, accompanied by DNA fragmentation. However, coexpression of bcl2 with c-myc in these cells led to a 10-fold increase in the number of live cells and a significant decrease in DNA fragmentation. Thus, Bcl-2 effectively inhibits Myc-induced apoptosis in serum-deprived Rat 1a fibroblasts without blocking entry into the cell cycle. These results imply that apoptosis serves as a protective mechanism to prevent tumorigenicity elicited by deregulated Myc expression. This protective mechanism is abrogated, however, by Bcl-2 and therefore may explain the synergism between Myc and Bcl-2 observed in certain tumor cells.
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PMID:Myc-mediated apoptosis is blocked by ectopic expression of Bcl-2. 845 20

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

The most common translocation in human lymphoma, t(14;18)(q32;q21), recombines the bcl-2 gene with the immunoglobulin (Ig) heavy-chain locus leading to the production of high levels of chimeric RNAs and the resulting 26 kDa bcl-2 protein. The oncogenic role of the bcl-2 gene has been shown by the suppression of a variety of programmed cell deaths (apoptosis). Bcl-2 is able to interact with other members of the bcl-2 family through at least one of its conserved dimerization domains. Although overproduction of the wild-type protein appears sufficient for conferring a selective growth or a survival advantage to hematopoietic cells, the mode of activation of the proto-oncogene remains to be elucidated. In a first step, we examined and quantitated the expression of the bcl-2 gene in primary biopsies of non-Hodgkin's lymphomas (NHL) as well as in cell lines derived from NHLs. The results show that bcl-2 expression is found in a variety of hematopoietic lineages, but is most strongly associated with the B cell lineage. Within the B cell lineage, the expression levels vary depending on the differentiation as well as on the t(14;18) rearranged status. The quantitative measurements show high steady-state mRNA levels in early and in t(14;18) arranged B cells, whereas bcl-2 expression decreases with further B cell maturation and differentiation. In a second step we analyzed the bcl-2 mRNA for secondary genetic alterations, which may alter regulatory regions rendering it more tumorigenic. For this purpose, we chose a combined RT-PCR/SSCP method in order to screen out mutations of alleles which are not expressed. Different migration patterns of SSCP products were found only in two cell lines and subsequent sequencing revealed that the functional domains are not affected. Our data suggest that the dimerization properties of this protein are preserved in tumor cells and that modifications of the bcl-2 gene by the somatic hypermutation mechanism are not involved and do not influence the pathobiology of NHL.
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PMID:Preservation of functional and regulatory domains of expressed bcl-2 genes in non-Hodgkin's lymphoma. 855 21

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

A variety of conflicting results appeared in the literature concerning the effect of dominant oncogenes on the sensitivity to irradiation and to anticancer agents in a number of cell lines of human and animal origin. In this report we provide evidence supporting the hypothesis that the tumor suppressor gene p53 and the apoptosis suppressor gene bcl2 modulate the effect of dominant oncogenes and that the effect of dominant oncogenes on resistance or sensitivity is dependent on the balance between the expression of p53 and bcl2.
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PMID:Dominant oncogenes, tumor suppressors, and radiosensitivity. 858 56

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


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