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 expression of the proto-oncogene bcl-2 was examined in a panel of 75 continuous human leukemia-lymphoma cell lines originated from different hematopoietic cell types. The presence of the bcl-2 protein, as evidenced by Western blotting, and its mRNA, as determined by Northern blotting, were not restricted to cells with the chromosomal translocation t(14;18)(q32;q21), but were also detected in a large number of cell lines without t(14;18). The amount of the bcl-2 protein and mRNA in the cell lines with t(14;18) was in the same order of magnitude as in other bcl-2 expressing cell lines of the same lineage, but without the translocation. Bcl-2 was found in all types of hematopoietic cell lines which were assigned to the following lineages based on their phenotypical characteristics: pre-B, B, plasma, T, myeloid, monocytic, erythroid-megakaryocytic and Hodgkin's lymphoma derived cell lines. The levels of accumulated mRNA and protein corresponded fairly well in most of the cell lines examined. Our results suggest the notion that bcl-2 expression is widely present in hematopoietic cell lines without restriction to single lineages and, in fact, clearly independent of the chromosomal aberration t(14;18). It is conceivable that bcl-2 expression is a common feature in established hematopoietic cell lines and may contribute to their unlimited growth in vitro.
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PMID:Expression of bcl-2 mRNA and protein in leukemia-lymphoma cell lines. 747 72

The induction of tumor cell differentiation represents an attractive strategy for the treatment of a wide range of malignancies. Differentiation of HL-60 promyelocytic leukemia cells towards neutrophils or monocytes has been shown to induce apoptotic cell death, which is inhibited by bcl-2 over-expression. However, the role of the bcl-2 gene family during erythroid differentiation of human leukemia cells remains unknown. We found that human erythroleukemia (HEL) and K562, two leukemia cell lines that undergo erythroid differentiation do not express Bcl-2, but express Bcl-XL, a related protein that functions as an inhibitor of apoptosis. Differentiation of HEL or K562 cells with inducers of erythroid differentiation (hemin, retinoic acid, or transforming growth factor-beta) was accompanied by progressive cell death and degradation of genomic DNA into oligonucleosomal fragments. The loss of cellular viability was associated with downregulation of bcl-xL mRNA and protein. In contrast, the levels of Bax, another Bcl-2 family member implicated in apoptosis remained unaltered. Constitutive expression of Bcl-XL by gene transfer inhibited apoptosis triggered by erythroid differentiation of HEL K562 cells. Yet, Bcl-XL did not alter the expression of epsilon-globin, which is induced during erythoid differentiation of HEL and K562 cells, arguing that apoptosis and differentiation can be uncoupled by Bcl-XL. These results indicate that Bcl-XL acts as an antiapoptosis protein in leukemia cells that undergo erythroid differentiation and that downregulation of bcl-x is a component of the apoptotic response that is coupled to differentiation in human leukemia cells.
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PMID:Apoptosis induced by erythroid differentiation of human leukemia cell lines is inhibited by Bcl-XL. 861 10

Erythropoietin (Epo), the hormone that is the principal regulator of red blood cell production, interacts with high-affinity receptors on the surface of erythroid progenitor cells and maintains their survival. Epo has been shown to promote cell viability by repressing apoptosis; however, the molecular mechanism involved is unclear. In the present studies we have examined whether Epo acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. We addressed this issue in HCD-57, a murine erythroid progenitor cell line that requires Epo for proliferation and survival. When HCD-57 cells were cultured in the absence of Epo, Bcl-2 and Bcl-XL but not Bax were downregulated, and the cells underwent apoptotic cell death. HCD-57 cells infected with a retroviral vector encoding human Bcl-XL or Bcl-2 rapidly stopped proliferating but remained viable in the absence of Epo. Furthermore, endogenous levels of bcl-2 and bcl-XL were downregulated after Epo withdrawal in HCD-57 cells that remained viable through ectopic expression of human Bcl-XL, further indicating that Epo specifically maintains the expression of bcl-2 and bcl-XL. We also show that HCD-57 rescued from apoptosis by ectopic expression of Bcl-XL can undergo erythroid differentiation in the absence of Epo, demonstrating that a survival signal but not Epo itself is necessary for erythroid differentiation of HCD-57 progenitor cells. Thus, we propose a model whereby Epo functions as a survival factor by repressing apoptosis through Bcl-XL and Bcl-2 during proliferation and differentiation of erythroid progenitors.
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PMID:Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. 878 12

Human chronic myelogenous leukemia-blast crisis K562 cells have been demonstrated to be relatively resistant to antileukemic drug-induced apoptosis. This has been attributed to the activity of p210bcr-abl tyrosine kinase present in the K562 cells, which is known to suppress drug-induced apoptosis. Recently, K562 cells have been shown to express the antiapoptosis Bcl-xL but not Bcl-2 proteins. To investigate the contribution of Bcl-xL toward resistance to drug-induced apoptosis, we created K562/Bcl-xS and K562/neo cells by electroporating the expression plasmids pSFFVneo-Bcl-xS and pSFFVneo, containing the bcl-xS and neomycin resistance genes, respectively, into K562 cells. K562/Bcl-xS but not K562/neo cells expressed the bcl-xS mRNA and p19Bcl-xS protein. In contrast, both cell types expressed equivalent levels of Bcl-xL, Bax, Bcl-2, Myc, retinoblastoma, p21cbor-abl, and p145abl proteins. A significant increase in the hemoglobin levels was observed in the K562/Bcl-xS compared with the K562/neo cells (P < 0.05). In addition, K562/Bcl-xS cells were significantly more sensitive than K562/neo cells to undergoing erythroid differentiation induced by low-dose 1-beta-D-arabinofuranosylcytosine (ara-C) and hexamethyl bisacetamide (P < 0.05), but not by all-trans-retinoic acid. Low-dose ara-C- or hexamethyl bisacetamide-induced differentiation was not associated with apoptosis of K562/Bcl-xS or K562/neo cells. Low-dose ara-C-induced erythroid differentiation was accompanied by conversion of the retinoblastoma protein to predominantly its underphosphorylated isoform as well as by down-regulation of Myc levels in K562/Bcl-xS and K562/neo cells. Importantly, exposure to high-dose ara-C (HIDAC; 100 microM ara-C for 4 h) caused internucleosomal DNA fragmentation and the morphological features of apoptosis in K562/Bcl-xS cells. These effects were modestly enhanced by cotreatment with HIDAC plus herbimycin A. In contrast, K562/neo cells were completely resistant to HIDAC- and herbimycin A-induced apoptosis. These results indicate that the expression of Bcl-xS induces erythroid differentiation and partially sensitizes chronic myelogenous leukemia-blast crisis-derived K562 cells to ara-C-induced differentiation and apoptosis.
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PMID:Enforced expression of Bcl-XS induces differentiation and sensitizes chronic myelogenous leukemia-blast crisis K562 cells to 1-beta-D-arabinofuranosylcytosine-mediated differentiation and apoptosis. 895 29

Based on previously published observations regarding the protective effects of interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) against gamma radiation, alkylating agents and ultraviolet radiation, we hypothesized that the protection against such DNA damaging treatments can be the result of a 'stress'-like response induced by these cytokines and mediated by early response cellular gene(s). By applying the mRNA differential display to RNA obtained from A549 lung carcinoma cell line that was incubated with 50 ng/ml IL-1 for 0, 1, 2, and 6 h, we identified several cDNA fragments that correspond to genes regulated by IL-1. The full length cDNA for one fragment was obtained using 5'RACE, cloned, sequenced, and found to be homologous to human A1, a Bcl-2-related gene. In this study, we report that the expression of human A1 is either absent or present at low levels in leukemic cells, while it is expressed in human bone marrow cells and abundant in peripheral blood progenitors. It is induced by IL-1 and TNF alpha in A549 lung carcinoma, bone marrow, and certain leukemic cells. A1 is also induced in leukemic cells during granulocytic or macrophage but not erythroid differentiation. In conclusion, this is the first demonstration that A1 is inducible by cytokines in human bone marrow and certain tumor cells as well as myeloid differentiation in leukemic cells.
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PMID:Human A1, a Bcl-2-related gene, is induced in leukemic cells by cytokines as well as differentiating factors. 920 81

Erythropoietin (EP) is required by late-stage erythroid progenitor cells to prevent apoptosis. Several lines of evidence suggest that it is this action of EP that regulates erythrocyte production in vivo. To study the control of apoptosis in mouse and human erythroblasts, the expression of members of the Bcl-2 family of proteins and the expression and activation of the apoptosis-linked cysteine protease Yama/CPP32/apopain were examined. These proteins have been implicated as regulators of apoptosis in several cell models. The Bcl-2 family members analyzed were Bcl-2, Bcl-X, Bax, Bad, Bak, A1, and Mcl-1. Bcl-X expression in proerythroblasts was highly EP-dependent. Bcl-X was strongly increased during the terminal differentiation stages of human and mouse erythroblasts, reaching maximum transcript and protein levels at the time of maximum hemoglobin synthesis. This increase in Bcl-X expression led to an apparent level of approximately 50 times the level in proerythroblasts. In contrast, neither mouse nor human erythroblasts expressed Bcl-2 transcript or protein. Bax and Bad proteins remained relatively constant throughout differentiation, but diminished near the time of enucleation. Bak protein was present in early erythroblasts, but diminished progressively during differentiation. EP deprivation in both mouse and human erythroblasts led to activation of the cysteine protease, apopain, as was indicated by cleavage of the proenzyme into its proteolytically active fragments. Apopain activation was detectable within 2 hours of EP deprivation in mouse erythroblasts. These findings suggest an important role for Bcl-X in late erythroid differentiation and for apopain in apoptosis of erythroblasts caused by deprivation of EP.
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PMID:The roles of Bcl-X(L) and apopain in the control of erythropoiesis by erythropoietin. 922 63

Differentiation- and lineage-related differences in the expression of two anti-apoptotic molecules, bcl-x and bcl-2, were examined using various human hematopoietic cell lines. Bcl-x was strongly expressed in cell lines with erythroid and megakaryocytic properties (K562, HEL, CMK, and Mo7E), and was moderately expressed in immature myeloid cell lines (KG-1 and KCL-22). Bcl-2 expression was relatively weak in these cells. On the other hand, bcl-x was not expressed in more mature myeloid cell lines (HL-60 and PL-21), but bcl-2 was strongly expressed in these cells and in monocytoid cell lines (U937, THP-1, and JOSK-I). We investigated the biological significance of high levels of bcl-x expression in erythroid and megakaryocytic lineage cells. When K562 cells were specifically differentiated into megakaryocytic lineage by phorbol ester, the amounts of bcl-x increased by 10-fold. In contrast, bcl-x was gradually downregulated during erythroid differentiation induced by cytosine arabinoside. Apoptosis was observed following erythroid differentiation of K562 cells, but it was not associated with megakaryocytic differentiation in consistent with the increase in bcl-x. Moreover, phorbol ester-induced megakaryocytic differentiation was facilitated by the overexpression of bcl-x in K562 cells. Finally, in situ hybridization revealed that bcl-x mRNA expression was strongest in megakaryocytes among normal bone marrow cells. These results suggest that bcl-x is a regulatory factor in the apoptosis and differentiation of megakaryocytes.
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PMID:Bcl-x is a regulatory factor of apoptosis and differentiation in megakaryocytic lineage cells. 950 20

Infection of erythroid-lineage cells by human parvovirus B19 is characterized by a gradual cytocidal effect. Accumulating evidence now implicates the nonstructural (NS1) protein of the virus in cytotoxicity, but the mechanism underlying the NS1-induced cell death is not known. Using a stringent regulatory system, we demonstrate that NS1 cytotoxicity is closely related to apoptosis, as evidenced by cell morphology, genomic DNA fragmentation, and cell cycle analysis with the human erythroleukemia cell line K562 and the erythropoietin-dependent megakaryocytic cell line UT-7/Epo. Apoptosis was significantly inhibited by an interleukin-1beta (IL-1beta)-converting enzyme (ICE)/CED-3 family protease inhibitor, Ac-DEVD-CHO (CPP32; caspase 3), whereas a similar inhibitor of ICE (caspase 1), Ac-YVAD-CHO, had no effect. Furthermore, stable expression of the human Bcl-2 proto-oncogene resulted in near-total protection from cell death in response to NS1 induction. Mutations engineered into the nucleoside triphosphate-binding domain of NS1 significantly rescued cells from NS1-induced apoptosis without having any effect on NS1-induced activation of the IL-6 gene expression which is mediated by NF-kappaB. Furthermore, using pentoxifylline, an inhibitor of NF-kappaB activation, we demonstrate that the NF-kappaB-mediated IL-6 activation by NS1 is uncoupled from the apoptotic pathway. This functional dissection indicates a complexity underlying the biochemical function of human parvovirus NS1 in transcriptional activation and induction of apoptosis. Our findings indicate that NS1 of parvovirus B19 induces cell death by apoptosis in at least erythroid-lineage cells by a pathway that involves caspase 3, whose activation may be a key event during NS1-induced cell death.
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PMID:Human parvovirus B19 nonstructural (NS1) protein induces apoptosis in erythroid lineage cells. 952 24

Transduction of hematopoietic stem cells with a novel retrovirus has allowed long-term expression of human Bcl-2 in multiple hematopoietic lineages. Thy-1.2lo Sca-1+ H-2Khi stem cells enriched from the bone marrow of 5-fluorouracil-treated (Ly5-2) mice were infected with the bcl-2 retrovirus and injected into (Ly5-1) irradiated recipients. Analysis at 5 months indicated that reconstitution of hematopoiesis occurred predominantly from donor-derived (Ly5-2+) stem cells and that, in half the mice (18 of 35), most blood cells derived from virally transduced stem cells. The level of Bcl-2 expression achieved with the retroviral vector approached that of a well-characterized transgenic vector and could be sustained for life in several blood cell lineages. In the 25 mice assessed at 10 months, human Bcl-2 was readily detectable in 62+/-22% of Ly5-2+ peripheral blood leukocytes. More detailed analysis of a cohort killed between 14 and 20 months established that human Bcl-2 protein could be detected in B and T lymphocytes, granulocytes, macrophages, and some immature erythroid cells. Furthermore, hematopoietic stem cells from the bone marrow of these mice maintained Bcl-2 expression in hematopoietic tissues of secondary recipients for at least another 19 months. These data provide clear evidence for efficient infection of primitive hematopoietic stem cells and for maintenance of proviral expression for over 2.5 years, the lifespan of mice. The level of exogenous Bcl-2 was sufficient to enhance survival of B and T lymphoid cells, granulocytes, and myeloid colony-forming cells cultured under suboptimal conditions, but hematopoiesis in the mice was not notably perturbed.
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PMID:Retroviral transduction of enriched hematopoietic stem cells allows lifelong Bcl-2 expression in multiple lineages but does not perturb hematopoiesis. 992 46

Erythropoietin (EPO) and its cell surface receptor (EPOR) play a central role in proliferation, differentiation, and survival of erythroid progenitors. Signals induced by EPO have been studied extensively by using erythroid as well as nonerythroid cell lines, and various controversial results have been reported as to the role of signaling molecules in erythroid differentiation. Here we describe a novel approach to analyze the EPO signaling by using primary mouse fetal liver hematopoietic cells to avoid possible artifacts due to established cell lines. Our strategy is based on high-titer retrovirus vectors with a bicistronic expression system consisting of an internal ribosome entry site (IRES) and green fluorescent protein (GFP). By placing the cDNA for a signaling molecule in front of IRES-GFP, virus-infected cells can be viably sorted by fluorescence-activated cell sorter, and the effect of expression of the signaling molecule can be assessed. By using this system, expression of cell-survival genes such as Bcl-2 and Bcl-XL was found to enhance erythroid colony formation from colony-forming unit-erythroid (CFU-E) in response to EPO. However, their expression was not sufficient for erythroid colony formation from CFU-E alone, indicating that EPO induces signals for erythroid differentiation. To examine the role of EPOR tyrosine residues in erythroid differentiation, we introduced a chimeric EGFR-EPOR receptor, which has the extracellular domain of the EGF receptor and the intracellular domain of the EPOR, as well as a mutant EGFR-EPOR in which all the cytoplasmic tyrosine residues are replaced with phenylalanine, and found that tyrosine residues of EPOR are essential for erythroid colony formation from CFU-E. We further analyzed the function of the downstream signaling molecules by expressing modified signaling molecules and found that both JAK2/STAT5 and Ras, two major signaling pathways activated by EPOR, are involved in full erythroid differentiation.
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PMID:Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells: functional analysis of signaling molecules by retrovirus-mediated expression. 1002 85


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