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 fusion gene AML1-ETO is the product of t(8;21)(q22;q22), one of the most common chromosomal translocations associated with acute myeloid leukemia. To investigate the impact of AML1-ETO on hematopoiesis, tetracycline-inducible AML1-ETO-expressing cell lines were generated using myeloid cells. AML1-ETO is tightly and strongly induced upon tetracycline withdrawal. The proliferation of AML1-ETO(+) cells was markedly reduced, and most of the cells eventually underwent apoptosis. RNase protection assays revealed that the amount of Bcl-2 mRNA was decreased after AML1-ETO induction. Enforced expression of Bcl-2 was able to significantly delay, but not completely overcome, AML1-ETO-induced apoptosis. Prior to the onset of apoptosis, we also studied the ability of AML1-ETO to modulate differentiation. AML1-ETO expression altered granulocytic differentiation of U937T-A/E cells. More significantly, this change of differentiation was associated with the down-regulation of CCAAT/enhancer binding protein alpha (C/EBPalpha), a key regulator of granulocytic differentiation. These observations suggest a dichotomy in the functions of AML1-ETO: (i) reduction of granulocytic differentiation correlated with decreased expression of C/EBPalpha and (ii) growth arrest leading to apoptosis with decreased expression of CDK4, c-myc, and Bcl-2. We predict that the preleukemic AML1-ETO(+) cells must overcome AML1-ETO-induced growth arrest and apoptosis prior to fulfilling their leukemogenic potential.
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PMID:Dichotomy of AML1-ETO functions: growth arrest versus block of differentiation. 1146 39

Accumulating evidence suggests that lack of balance between proliferation and apoptosis may lead to clonal expansion and cancer emergence. In diffuse large B cell lymphoma (DLBCL), survivin expression by tumor cells has been recently described as a poor prognostic marker. We assessed the relationship between survivin gene up-regulation and several other factors involved in either cell cycle or apoptosis control. The expression of 34 genes from 27 cases of DLBCL with typical IPI factor-related poor prognostic outcome was analyzed by RNase protection assay. Using non-neoplastic tissues and low grade lymphomas as control, survivin expression was high in 80% of the cases without significant relation to patient overall survival (P = 0.64). However, the expression of several genes encoding for cell cycle inhibitors, cyclins, Bcl-2 or IAP family factors was significantly associated with the survivin up-regulation. Gene expression profiling showed that both survivin and cyclin B expression can define two subgroups of DLBCL: the previously described germinal center-like and activated B-like lymphomas, determined by protein expression analysis. We also identified a preferential survivin-cyclin B relationship (P = 0.017), suggesting that cyclin B over-expression, when linked to survivin over-expression in aggressive forms of lymphoma, might demonstrate a specific G2/M transition promotion.
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PMID:Relationship between expression of genes involved in cell cycle control and apoptosis in diffuse large B cell lymphoma: a preferential survivin-cyclin B link. 1196 Mar 56

Bendamustine is a novel cytostatic agent, with activity in non-Hodgkin's lymphomas including B-chronic lymphocytic leukemia (B-CLL). The knowledge about its mode of action, however, is still limited. Here, we investigated the in vitro ability of bendamustine to induce apoptosis on freshly isolated peripheral lymphocytes in B-CLL and analyze the potential underlying mechanisms of action for inducing apoptosis. In CLL cells taken from 37 previously treated and untreated CLL patients, we investigated the influence of bendamustine alone, and in combination with fludarabine, on the induction of apoptosis and changes of Bcl-2 and Bax expression on mRNA and protein level using the RNase protection assay or flow cytometry, respectively. Apoptotic cells were determined with flow cytometry using the fluorescent DNA-binding agent 7-ADD. Using bendamustine alone in concentrations from 1 microg/ml to 50 microg/ml, a dose- and time-dependent manner of cytotoxicity from 30.4% to 94.8% after 48 h could be observed. The LD50 for untreated and pretreated CLL cells was 7.3 or 4.4 microg/ml, respectively. The median apoptotic rate was similar in both groups. The combination of bendamustine with fludarabine led to a highly synergistic effect in inducing apoptosis, which was 150% higher than expected for bendamustine plus fludarabine. The level of the initial Bcl-2 and Bax protein and the m-RNA expression remained unchanged during the incubation with bendamustine. In conclusion, this study demonstrates for the first time the in vitro efficacy of bendamustine in inducing apoptosis in B-CLL cells alone and in combination with fludarabine.
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PMID:In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia. 1235 63

Fibroblast apoptosis is crucial to the resolution of fibrosis. However, the mechanisms by which these cells undergo apoptosis are not well known. Because interleukin (IL)-6 and IL-11 may alter repair and remodeling processes, we hypothesized that they may play a role in idiopathic pulmonary fibrosis (IPF). We investigated the effects of these cytokines on Fas-induced apoptosis using primary lung fibroblasts from three patients with IPF (IPF-Fb) and three subjects without lung disease (normal-Fb). IPF-Fb were resistant to Fas-induced apoptosis compared with normal-Fb (P < 0.01). Using RNase protection assays, we showed that IL-6 enhanced Fas-induced apoptosis and expression of Bax in normal-Fb, but inhibited apoptosis and induced expression of Bcl-2 in IPF-Fb. Densitometry of Western blots revealed a Bcl-2/Bax ratio 0.15 +/- 0.01 in normal-Fb compared with 12.05 +/- 1.0 in IPF-Fb. Upregulation of Bcl-2 in normal-Fb and Bax in IPF-Fb were both STAT-3-dependent. Inhibition of extracellular signal-regulated kinase had no effect in normal-Fb, but reversed the antiapoptotic effect of IL-6 in IPF-Fb. IL-11 inhibited Fas-induced apoptosis and increased Bcl-2 expression in both normal-Fb and IPF-Fb. These results suggest that altered IL-6 signaling in IPF-Fb may enhance the resistance of these cells to apoptosis and contribute to a profibrotic effect of IL-6 in IPF.
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PMID:Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs. 1271 76

Interleukin-6 (IL-6) is a major survival factor for malignant plasma cells involved in multiple myeloma. Using an RNase protection assay, we looked for gene expression of 10 anti- and proapoptotic Bcl-2-family proteins in 12 IL-6-dependent human myeloma cell lines (HMCL). A high Mcl-1 gene expression was found in all HMCLs and the other genes were variably expressed. Out of the 10 Bcl-2-family members, only the Mcl-1 gene was regulated by IL-6. Upon starvation of IL-6, Mcl-1 gene expression decreased in association with myeloma cell apoptosis and was upregulated after adding IL-6 again in association with myeloma cell survival. A constitutive Mcl-1 expression was induced with an Mcl-1-GFP retrovirus in two IL-6-dependent HMCLs. The Mcl-1 HMCLs have a marked reduced apoptosis upon IL-6 starvation compared to HMCLs transduced with control GFP retrovirus and may grow without adding IL-6. These data emphasize the major role of Mcl-1 antiapoptotic protein in the IL-6-induced survival of human myeloma cells.
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PMID:A major role for Mcl-1 antiapoptotic protein in the IL-6-induced survival of human myeloma cells. 1277 46

Respiratory syncytial virus (RSV) is an important cause of respiratory tract disease worldwide, especially in the pediatric population. For viruses in general, apoptotic death of infected cells is a mechanism for reducing virus replication. Apoptosis can also be an important factor in augmenting antigen presentation and the host immune response. We examined apoptosis in response to RSV infection of primary small airway cells, primary tracheal-bronchial cells, and A549 and HEp-2 cell lines. The primary cells and the A549 cell line gave generally similar responses, indicating their appropriateness as models in contrast to HEp-2 cells. With the use of RNase protection assays with probes representing 33 common apoptosis factors, we found strong transcriptional activation of both pro- and antiapoptotic factors in response to RSV infection, which were further studied at the protein level and by functional assays. In particular, RSV infection strongly up-regulated the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its functional receptors death receptor 4 (DR4) and DR5. Furthermore, RSV-infected cells became highly sensitive to apoptosis induced by exogenous TRAIL. These findings suggest that RSV-infected cells in vivo are susceptible to killing through the TRAIL pathway by immune cells such as natural killer and CD4(+) cells that bear membrane-bound TRAIL. RSV infection also induced several proapoptotic factors of the Bcl-2 family and caspases 3, 6, 7, 8, 9, and 10, representing both the death receptor- and mitochondrion-dependent apoptotic pathways. RSV also mediated the strong induction of antiapoptotic factors of the Bcl-2 family, especially Mcl-1, which might account for the delayed induction of apoptosis in RSV-infected cells in the absence of exogenous induction of the TRAIL pathway.
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PMID:Respiratory syncytial virus infection sensitizes cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand. 1291 32

Using morphological and molecular approaches, we characterized cisplatin-induced cell necrosis and apoptosis in rat kidney. Male Sprague-Dawley rats ( n=5 per group) received a single intraperitoneal injection of either cisplatin (5 mg/kg) or saline, and were killed on day 5. Functionally, cisplatin-treated rats developed polyuric acute renal failure. Morphologically, kidneys of cisplatin-treated rats showed overt tubular necrosis associated with apoptosis in the corticomedullary junction. Cell necrosis was segment-specific and was distributed in radial fashion at the corticomedullary junction. The apoptosis was limited to discrete cells in apparently intact tubules in the vicinity of the necrosed tubules. The apoptotic changes were confirmed by TUNEL (TdT-mediated deoxyuridine triphosphate nick-end labeling) and staining for cleaved caspase-3. Analysis of outer medullary tissue for apoptosis-related molecules by RNase protection assay revealed a significant increase in the expression of pro-apoptotic mRNAs (caspases 1, 2, and 8, and Bax) in cisplatin-treated rats. On the other hand, the expression of mRNA for the anti-apoptotic Bcl-2 did not change, resulting in a decrease in relative ratio of Bcl-2/Bax, and thus favoring apoptosis. The above changes were paralleled by a marked increase in caspase-3 precursor, the executioner protease. Furthermore, these pro-apoptotic molecular changes were associated with a 3-fold increase in the activity of JNK1 in the outer medulla, but not in the cortex, of cisplatin-treated rat kidneys, localizing to the site of maximal apoptosis. Upregulation of JNK1 activity in the outer medulla was not accompanied by changes in the activities of ERK or p38 kinase. In conclusion, these data suggest that cisplatin-induced apoptotic cell death in native kidney may be mediated by cooperative activation of the JNK1 pathway and Bax in the outer medulla.
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PMID:Cellular and molecular studies on cisplatin-induced apoptotic cell death in rat kidney. 1455 73

Various chemotherapeutic agents have been shown to sensitize cancer cells to members of the tumor necrosis factor (TNF) family. However, it is unclear whether sensitization by chemotherapeutic agents involves the transcriptional regulation of apoptosis-related genes. In this study, we investigated mRNA regulation of TNF family receptors and Bcl-2 family members after treating the murine colon cancer cell line, CT26, with various apoptosis inducers. We found that treatment with cycloheximide, a protein synthesis inhibitor, remarkably increased CD40 mRNA levels by semi-quantitative RT-PCR. Other protein synthesis inhibitors, such as anisomycin and emetine, also enhanced CD40 mRNA expression, which was significantly blocked by a NF-kappaB antagonist and a p38 MAP kinase antagonist. After treatment with cycloheximide, and further cultivation in fresh medium, CD40 protein levels were found to increase by flow cytometry. Additionally, we found that cycloheximide treatment appeared to downregulate the Bcl-xL mRNA level but not the Bax mRNA level by RNase protection assay. Because the upregulation of CD40 mRNA and the downregulation of Bcl-xL correlated with CT26 cell death, our results suggest that chemotherapeutic agents, including cycloheximide, may exert their synergistic effects on the TNF family treatment of cancer cells by regulating the mRNA levels of apoptosis-related genes.
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PMID:Transcriptional regulation of TNF family receptors and Bcl-2 family by chemotherapeutic agents in murine CT26 cells. 1474 99

Cell proliferation and apoptosis are controlled by tightly orchestrated signaling pathways that culminate in transcriptional activation/repression of multiple proteins. Dysregulation of cell cycle and/or apoptosis control may lead to genomic instability, neoplastic transformation and tumor progression. Under certain conditions, some hexavalent chromium [Cr(VI)] compounds are toxic and carcinogenic in the human respiratory tract, and we have shown that they induce apoptosis and/or cell cycle arrest in a p53-dependent fashion. There is increasing evidence linking extracellular signal-regulated kinase (ERK) activation with the DNA damage response, by both p53-dependent and -independent mechanisms. Here, the aim was to study the effect of Cr(VI) transcriptional regulation of key cell cycle inhibitors and pro- and anti-apoptotic proteins, as well as the role of ERK activation in the Cr(VI) genotoxic response. Diploid human lung fibroblasts were incubated with 3-9 uM Na2CrO4, and RNA was isolated at 4, 8, and 24 h, as well as 24 h after Cr(VI) exposure was terminated (recovery). mRNA expression was quantitated by RNase protection assay with a 32P-labeled multi-transcript probe containing gene sequences for the cdk inhibitors, p21waf1/cip1, p27kip1, p16INK4a, p15INK4b; the pro-apoptotic proteins bcl-XS and bax; the anti-apoptotic proteins bcl-W, bcl-XL, and bcl2, GADD45, and cyclin A. In general, bcl-W and bcl-XL expression were both downregulated after Cr exposure, to around 50% at 24 h, which was more pronounced after the recovery period. At Cr(VI) concentrations < or = 6 uM, bcl2 expression was upregulated. Of particular interest is that bax expression was reduced, in a dose and time-dependent fashion, however that of bcl-XS was elevated by nearly 3-fold after 8 h, and declined to control levels at the end of the recovery period. Expression of GADD45 and p21 were both upregulated by 2-fold at 8 h, but declined to control levels during recovery. Neither the expression of p27 nor that of p16 were apparently affected by Cr(VI) exposure, however the expression of p15 was markedly increased after exposure to all concentrations of Cr(VI). Finally, the expression of cyclin A was decreased after 24 h Cr(VI) exposure. Cr(VI) induced a transient burst of ERK activity (2-6-fold over control) around 0.5-3 h after exposure. However, inhibition of ERK activation with PD98059 had no effect on the Cr-induced alterations in gene expression. Moreover, Cr(VI)-induced clonogenic lethality, as assessed after 24 h exposure to 1 and 2 uM Cr(VI), was also not affected by ERK inhibition. These data suggest that both p53-dependent and -independent apoptotic and growth-inhibitory pathways are markedly affected by Cr(VI) exposure. However, the ability of Cr(VI) to affect key apoptotic and growth arresting genes, and thus clonogenic lethality, appears to be independent of ERK. Continued investigation into the cellular and molecular mechanisms of Cr(VI)-induced cell cycle and apoptosis control should further the understanding of Cr(VI)-associated carcinogenesis.
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PMID:Induction of pro-apoptotic and cell cycle-inhibiting genes in chromium (VI)-treated human lung fibroblasts: lack of effect of ERK. 1497 55

Bcl-2 family members either negatively or positively regulate the apoptotic threshold of cells. Bcl-xES (extra short), a novel Bcl-x member, possesses a unique combination of BH4 and BH2 domains as well as a COOH-terminal hydrophobic transmembrane anchor domain. Bcl-xES contains sequences of hydrophobic alpha-6 helices but lacks sequences of alpha-5 helices, suggesting that it does not have pore channel-forming activity but functions uniquely as a trapping protein. mRNA expression analysis by reverse transcriptase-polymerase chain reaction and RNase protection assay reveal that Bcl-xES is expressed in a variety of human cancer cell lines and human tumors, including bone marrow from patients with acute lymphoblastic leukemia. Bcl-xES expression is much less pronounced in some specimens of normal human tissues, including the breast, ovary, testis and lung. Stable, transfected human B lymphoma Namalwa variant cells expressing Bcl-xES were derived to investigate its role in apoptosis. Bcl-xES had a preventive effect on cell death induced by tumor necrosis factor-alpha and various concentrations of anticancer drugs, including camptothecin, etoposide and cisplatin. Its protective action on cell death was correlated with the inhibition of mitochondrial cytochrome c release and caspase activation. In a yeast two-hybrid system, Bcl-xES interacted with most Bcl-2 family members, including those containing only a BH3 domain, and with the Ced-4 homolog Apaf-1. Co-immunoprecipitation and gel filtration chromatography experiments suggest that Bcl-xES delays drug-induced apoptosis by disturbing the formation of Bax oligomers and preventing cytochrome c release, but also by interacting with Apaf-1 and inhibiting procaspase-9 activation, thus averting the apoptogenic proteolytic caspase cascade and cell death.
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PMID:Bcl-xES, a BH4- and BH2-containing antiapoptotic protein, delays Bax oligomer formation and binds Apaf-1, blocking procaspase-9 activation. 1504 82


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