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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bcl-2 and its homologue, bcl-xL, encode membrane-associated proteins that suppress programmed cell death of hematopoietic cell lines after growth factor withdrawal, and are expressed in hematopoietic precursor cells. To better understand the maintenance of long-term survival in the hematopoietic stem cell population, we evaluated the expression patterns of Bcl-2 and Bcl-x in primitive hematopoietic precursor populations. Hematopoietic precursor cells expressing CD34 (CD34+) and lacking maturation-linked surface antigens (lin-) were isolated from adult human bone marrow using two-color immunofluorescence cell sorting and fractionated on the basis of forward light scatter characteristics into blast-sized and small to medium lymphocyte-sized cell populations. Bcl-2 expression was shown in 78% to 90% of CD34+ lin- blast-sized cells versus less than 10% of small to medium lymphocyte-sized CD34+ lin- cells by immunohistochemical analysis. Small to medium lymphocyte-sized CD34+ lin- cells were further enriched for primitive precursors by selecting cells that lacked expression of CD38 (CD34+ lin- CD38-). In parallel experiments, only 1% to 4% of CD34+ lin- CD38- cells expressed Bcl-2, whereas 45% to 56% of these cells generated colony-forming cells. In contrast, > or = 94% of cells in all bone marrow subpopulations studied expressed Bcl-x protein. Both alternatively spliced bcl-x transcripts, bcl-xL and bcl-xs, were present. Our data show that the most primitive hematopoietic precursors express Bcl-x but not Bcl-2. Thus, the functional bcl-2 homologue, bcl-xL, may be essential for the long-term survival of the hematopoietic stem cell population.
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PMID:Primitive human hematopoietic precursors express Bcl-x but not Bcl-2. 754 99

Most examples of cell death in animals are controlled by a genetic program that is activated within the dying cell. The apoptotic process is further regulated by a set of genes that act as repressors of cell death. Of these, bcl-2 is expressed in a variety of embryonic and postnatal tissues which suggests a critical role for bcl-2 in organogenesis and tissue homeostasis. Surprisingly, mutant mice with targeted disruption of bcl-2 appear normal at birth and complete maturation of lymphoid tissues before succumbing to fulminant lymphopenia and polycystic renal disease by 2-5 weeks of age. This suggests that there may be genes other than bcl-2 that can regulate apoptosis during development. To begin to investigate this possibility, we have cloned and characterized the murine bcl-x gene, whose human counterpart displays striking homology to bcl-2. The predicted murine bcl-xL gene product exhibits a high level of amino acid identity (97%) to its human counterpart. Just like Bcl-2, the murine bcl-xL gene product can act as a dominant inhibitor of cell death upon growth factor withdrawal. In addition, the bulk of the bcl-xL product localizes to the periphery of mitochondria as assessed by a bcl-xL-tag expression system, suggesting that both Bcl-2 and Bcl-xL proteins prevent cell death by a similar mechanism. bcl-xL is the most abundant bcl-x mRNA species expressed in embryonic and adult tissues. The levels of bcl-xL mRNA appear higher than those of bcl-2 during embryonal development and in several adult organs including bone marrow, brain, kidney and thymus. In addition to bcl-xL, we have identified another form of bcl-x mRNA, bcl-x beta, that results from an unspliced bcl-x transcript. bcl-x beta mRNA is expressed in various embryonic and postnatal tissues. Surprisingly, the expression of bcl-xS (a negative regulator of programmed cell death) was undetectable by a sensitive S1-nuclease assay and polymerase chain reaction analysis of mouse tissues. Based on its tissue and developmental patterns of expression, it appears that bcl-x may play an important role in the regulation of cell death during development and tissue homeostasis.
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PMID:bcl-XL is the major bcl-x mRNA form expressed during murine development and its product localizes to mitochondria. 760 90

Bcl-X protein, which is related to Bcl-2, is present essentially in the nervous system and the immune system, under 2 different forms: Bcl-XL, like Bcl-2, is able to prevent apoptotic death of cultured lymphocytes; in contrast, Bcl-XS, which differs from the former one by a deletion of 63 amino acids in the region of greatest homology between Bcl-XL and Bcl-2, is unable to prevent this apoptotic death and even counteracts the protective effect of Bcl-2. It has been reported that the adult nervous system contains exclusively the RNA encoding Bcl-XL whereas the immune system would contain exclusively the RNA encoding Bcl-XS. We show here, by using reverse transcription coupled to PCR, that adult rat brain contains not only the RNA encoding Bcl-XL but also the RNA encoding Bcl-XS. Similarly we show that human lymphocytes, whether infected or not by the HIV, contain both forms of Bcl-X messenger RNA (mRNA). Furthermore we have observed that both forms of mRNA are present in adult rat liver and in cultured mouse hepatocytes. All these results have been confirmed by hybridizing the PCR products transferred to a nylon membrane with a probe specific of Bcl-XL or a non discriminative probe.
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PMID:Presence of the long and the short forms of Bcl-X in several human and murine tissues. 767 Sep 99

Previous studies have implicated the bcl-2 protooncogene as a potential regulator of neuronal survival. However, mice lacking functional bcl-2 exhibited normal development and maintenance of the central nervous system (CNS). Since bcl-2 appears dispensable for neuronal survival, we have examined the expression and function of bcl-x, another member of the bcl-2 family of death regulatory genes. Bcl-2 is expressed in neuronal tissues during embryonic development but is down-regulated in the adult CNS. In contrast, Bcl-xL expression is retained in neurons of the adult CNS. Two different forms of bcl-x mRNA and their corresponding products, Bcl-xL and Bcl-x beta, were expressed in embryonic and adult neurons of the CNS. Microinjection of bcl-xL and bcl-x beta cDNAs into primary sympathetic neurons inhibited their death induced by nerve growth factor withdrawal. Thus, Bcl-x proteins appear to play an important role in the regulation of neuronal survival in the adult CNS.
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PMID:bcl-x is expressed in embryonic and postnatal neural tissues and functions to prevent neuronal cell death. 775 2

Upon cytokine withdrawal, interleukin (IL) 6-dependent murine plasmacytoma/hybridoma (myeloma) cells die in a way characteristic of apoptosis. Although gene transfer-mediated elevation in Bcl-2 protein levels has been demonstrated to repress a number of apoptotic death programs, it has been reported that ectopic bcl-2 expression is unable to prolong the survival of IL-6-deprived myeloma cells. In view of the recent identification of Bax as a protein that antagonizes the anti-apoptotic function of Bcl-2, we sought to determine whether the inability of transfected bcl-2 to protect against myeloma cell apoptosis might simply be due to insufficient levels of Bcl-2 protein produced to counteract this inhibitor. We show here that high-level expression of an exogenous bcl-2 gene, introduced into IL-6-dependent B9 myeloma cells via retroviral or bovine papilloma virus-based vectors, is indeed able to suppress apoptotic death following cytokine deprivation, with the extent of protection provided correlating with the amount of Bcl-2 protein synthesized in relation to the amount of endogenous Bax protein present in the cells. Of note, however, we found that IL-6-mediated suppression of B9 apoptosis does not involve induction of endogenous bcl-2 expression but is associated instead with the upregulation of cellular bcl-x mRNA and Bcl-xL protein. These results thus extend the apoptotic death mechanisms that are inhibitable by both bcl-2 and bcl-xL to include that operative in IL-6-dependent cells and suggest that apoptosis in other cell types using the gp130 subunit of the IL-6 receptor might also be bcl-2 regulable or bcl-xL dependent.
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PMID:Prevention of myeloma cell apoptosis by ectopic bcl-2 expression or interleukin 6-mediated up-regulation of bcl-xL. 775 73

bcl-x is a new member of the bcl-2 gene family and is highly expressed in neural tissues. The present study was designed to determine the expression of the bcl-x gene products in neuroblastoma (NB) and their role in the modulation of chemotherapy-induced apoptosis. Twenty-seven NB cell lines were screened by quantitative immunoprecipitation for Bcl-xL, Bcl-xS, and Bcl-2 expression. None of the cell lines expressed Bcl-xS. Twenty-four of 27 (88%) of the NB cell lines expressed Bcl-xL and 21 of 27 (78%) were positive for Bcl-2. The level of Bcl-xL and Bcl-2 expression was variable among the lines analyzed. Bcl-2 expression was restricted to cells of chromaffin lineage, whereas Bcl-xL was seen in both chromaffin and nonchromaffin lines. To determine whether Bcl-xL could mediate chemotherapy resistance, a NB cell line expressing negligible levels of Bcl-xL was transfected with a bcl-xL expression vector, and unique clones were generated expressing variable levels of Bcl-xL. Cells were treated either with cisplatinum (CP), 4-hydroperoxy-cyclophosphamide (4-HC), or etoposide (VP-16) to induce apoptosis, and cell viability and DNA degradation were determined. Following treatment with CP or 4-HC, Bcl-xL-expressing cells showed significantly increased viability as compared to vector-transfected controls (P < 0.005). Flow cytometric analysis of propidium iodide-stained nuclei following CP or 4-HC treatment revealed significantly increased DNA degradation in controls as compared to Bcl-xL-expressing lines (P < 0.004). DNA analysis by pulsed-field gel electrophoresis revealed high molecular weight (approximately 40 kb) DNA degradation in controls, whereas the DNA in cells expressing Bcl-xL was largely intact. In contrast to CP and 4-HC, results with VP-16 revealed a short-term delay in the onset of apoptosis in Bcl-xL-expressing cells with no long-term survival advantage. The results of these studies indicate Bcl-xL is expressed in NB cells and functions in a manner analogous to Bcl-2 by inhibiting chemotherapy-induced apoptosis.
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PMID:Bcl-xL is expressed in neuroblastoma cells and modulates chemotherapy-induced apoptosis. 778 Sep 71

Interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF) induce DNA synthesis and suppress apoptosis of hematopoietic cells. IL-3/GM-CSF exert pleiotropic functions by activating multiple signaling cascades through distinct domains of the common receptor subunit. As we previously reported, the Ras signaling pathway plays a pivotal role in suppressing apoptotic death rather than stimulating DNA synthesis in IL-3 dependent hematopoietic cells. In order to clarify the molecular basis of Ras-induced cell survival, we investigated the effect of Ras activation on the expression of Bcl-2 and its related molecules. Activation of the Ras pathway by using an inducible oncogenic Ras resulted in the rapid up-regulation of bcl-2 and bcl-xL, and the level of expression was nearly equivalent to that observed in growing cells. On the other hand, expression of bax, an antagonistic bcl-2 homologue, was not affected by oncogenic Ras or IL-3-deprivation. Thus, the Ras pathway regulates the expression of Bcl-2 and its related survival protein, and this appears to underlie the mechanism by which IL-3/GM-CSF inhibit apoptosis through activation of the Ras pathway.
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PMID:Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells. 778 65

Recent studies have proposed that tumor necrosis factor alpha (TNF-alpha) and ionizing radiation induce apoptosis by activating hydrolysis of sphingomyelin to ceramide. Bcl-2 and a related gene, Bcl-X, inhibit several forms of apoptosis. Herein, we report that internucleosomal DNA fragmentation, characteristic of apoptosis and induced by ionizing radiation, is accompanied by concomitant decreases in Bcl-2 and Bcl-X mRNA levels in HL-60 and U-937 human leukemia cells. Apoptotic DNA fragmentation after exposure to TNF-alpha and C2-ceramide was also associated with down-regulation of Bcl-2 mRNA in HL-60 and U-937 cells, while Bcl-X mRNA production was unaffected. These results suggest that modulation of Bcl-2 gene expression may be a target for ceramide-mediated apoptosis following exposure to ionizing radiation and TNF-alpha. Changes in Bcl-2 expression may be the basis for the interactive killing observed between radiation and TNF-alpha in some human and tumor cells.
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PMID:Suppression of Bcl-2 messenger RNA production may mediate apoptosis after ionizing radiation, tumor necrosis factor alpha, and ceramide. 786 10

The in vivo patterns of bcl-X gene expression were assessed in human and mouse tissues using an immunohistochemical approach. Polyclonal antisera were raised against synthetic peptides corresponding to amino acids 46-66 and 61-79 of the human Bcl-X protein and were shown to be specific for detection of human and mouse Bcl-X-L and Bcl-X-S proteins by immunoblotting. Bcl-X immunoreactivity was detected in a wide variety of cell types and was typically present in the cytosol in a punctate pattern suggestive of association with intracellular organelles. Among the cell types with prominent Bcl-X immunostaining were: (a) a variety of neuronal populations in the brain as well as sensory neurons in dorsal root ganglia; (b) cortical (but not medullary) thymocytes and activated lymphocytes and plasma cells in lymph nodes; (c) several types of cells in the bone marrow, including megakaryocytes, red cell precursors, and some types of differentiating myeloid cells; (d) reproductive tissues, including the spermatocytes and spermatids in the testes and germinal epithelium of the ovary; and (e) a variety of epithelial cells including mammary epithelium, the secretory epithelial and basal cells of the prostate, uterine endometrium, gastric and intestinal epithelial cells, renal tubule epithelium, and differentiated keratinocytes in the upper layers of the epidermis but not in the basal cells. In many cases, these patterns of Bcl-X expression were strikingly different from those reported previously for Bcl-2, suggesting that Bcl-X and Bcl-2 regulate cell life and death at different stages of cell differentiation through tissue-specific control of their expression.
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PMID:Immunohistochemical analysis of in vivo patterns of Bcl-X expression. 792 84

Interactions of the Bcl-2 protein with itself and other members of the Bcl-2 family, including Bcl-X-L, Bcl-X-S, Mcl-1, and Bax, were explored with a yeast two-hybrid system. Fusion proteins were created by linking Bcl-2 family proteins to a LexA DNA-binding domain or a B42 trans-activation domain. Protein-protein interactions were examined by expression of these fusion proteins in Saccharomyces cerevisiae having a lacZ (beta-galactosidase) gene under control of a LexA-dependent operator. This approach gave evidence for Bcl-2 protein homodimerization. Bcl-2 also interacted with Bcl-X-L and Mcl-1 and with the dominant inhibitors Bax and Bcl-X-S. Bcl-X-L displayed the same pattern of combinatorial interactions with Bcl-2 family proteins as Bcl-2. Use of deletion mutants of Bcl-2 suggested that Bcl-2 homodimerization involves interactions between two distinct regions within the Bcl-2 protein, since a LexA protein containing Bcl-2 amino acids 83-218 mediated functional interactions with a B42 fusion protein containing Bcl-2 amino acids 1-81 but did not complement a B42 fusion protein containing Bcl-2 amino acids 83-218. In contrast to LexA/Bcl-2 fusion proteins, expression of a LexA/Bax protein was lethal to yeast. This cytotoxicity could be abrogated by B42 fusion proteins containing Bcl-2, Bcl-X-L, or Mcl-1 but not those containing Bcl-X-S (an alternatively spliced form of Bcl-X that lacks a well-conserved 63-amino acid region). The findings suggest a model whereby Bax and Bcl-X-S differentially regulate Bcl-2 function, and indicate that requirements for Bcl-2/Bax heterodimerization may be different from those for Bcl-2/Bcl-2 homodimerization.
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PMID:Interactions among members of the Bcl-2 protein family analyzed with a yeast two-hybrid system. 793 47


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