Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of the phenotypically immature B cell lymphoma WEHI-231 with anti-IgM induces G1 arrest followed by apoptotic cell death, which can be reversed by stimulation via the CD40 receptor. Here, we show that cells expressing bcl-xL (WEHI-bcl-xL) arrest at G0/G1 following culture with anti-IgM but do not undergo apoptosis. These arrested cells can be induced to reenter the cell cycle by ligation of CD40. We have therefore used these cells as a model to study the regulation of the transcription factor E2F, which is critically involved in transit through the cell cycle. We found that anti-IgM treatment induces the appearance of an inhibitory DNA binding complex containing the pRB-related pocket protein p130 together with E2F and a concomitant decrease in "free" E2F, consisting of E2F1 and its partner DP1; these effects were reversed following stimulation via CD40. These changes in free E2F levels were regulated by changes in E2F1 gene transcription, which is at least partly a result of control of E2F1 promoter activity through its E2F binding sites. Transient transfection experiments showed that either E2F1 or the viral oncoprotein E1A, which sequesters pocket proteins, including p130, overcame anti-IgM-induced cell cycle arrest in WEHI-bcl-xL. Taken together, these results indicate that in WEHI-231 sIgM ligation induces the accumulation of hypophosphorylated p130 with consequent inhibition of E2F1 gene transcription and cell cycle arrest. Conversely, ligation of CD40 causes hyperphosphorylation of p130, thereby releasing the repression of E2F1 and other E2F-regulated genes, enabling the cells to reenter the cycle. These results, therefore, provide novel insights into the mechanisms whereby antigen receptors on immature B cells deliver inhibitory signals (leading to negative selection of self-reactive B cells) and how these signals can be modulated by positive signals generated via CD40.
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PMID:Modulation of E2F activity via signaling through surface IgM and CD40 receptors in WEHI-231 B lymphoma cells. 954 52

The expression of Bcl-2 family proteins (Bcl-2, Bcl-X, Bcl-XL, Bcl-Xs, BAX, BAD, MCL-1) and of Interleukin-1 converting enzyme (ICE)-related proteins (ICE, CPP32, ICH- 1) was analyzed in acute leukemia cells by flow cytometry. Most proteins studied were detectable in cell lines such as KG1a, HL60, K562 (myeloblastic), REH, RAJI and MOLT4 (lymphoblastic) and VAL (B-cell lymphoma). However, BCL-Xs and BAK were weakly expressed in K562, as were Bcl-X, BAD and BAK in the VAL line. In acute myeloid leukemia (66 cases studied), the proteins were expressed in most cases in a high percentage of cells, especially BAX and CPP32, without correlation with hematological characteristics. However, Bcl-2 was expressed in a higher percentage of cells in FAB M1 and M5 cases, and in CD34-positive cases, whereas Bcl-Xs was more frequently expressed in M3 cases. No differences were observed regarding fluorescence intensity. Higher percentages of Bcl-2-positive cells were associated with low remission rate, while expression of Bcl-Xs was predictive of high remission rate. In acute lymphoblastic leukemia (36 cases), all proteins studied were expressed in a majority of cases. Bcl-Xs was more frequently detected in T-cell type, and was also associated with a higher remission rate. These results suggest that apoptosis-controlling proteins may have a role in the pathogenesis and response to therapy of acute leukemia.
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PMID:Expression of apoptosis-controlling proteins in acute leukemia cells. 1034 77

Cytochrome c released from mitochondria into the cytoplasm plays a critical role in many forms of apoptosis by stimulating apoptosome formation and subsequent caspase activation. However, the mechanisms regulating cytochrome c apoptotic activity are not understood. Here we demonstrate that cytochrome c is nitrosylated on its heme iron during apoptosis. Nitrosylated cytochrome c is found predominantly in the cytoplasm in control cells. In contrast, when cytochrome c release from mitochondria is inhibited by overexpression of the anti-apoptotic proteins B cell lymphoma/leukemia (Bcl)-2 or Bcl-X(L), nitrosylated cytochrome c is found in the mitochondria. These data suggest that during apoptosis, cytochrome c is nitrosylated in mitochondria and then rapidly released into the cytoplasm in the absence of Bcl-2 or Bcl-X(L) overexpression. In vitro nitrosylation of cytochrome c increases caspase-3 activation in cell lysates. Moreover, the inhibition of intracellular cytochrome c nitrosylation is associated with a decrease in apoptosis, suggesting that cytochrome c nitrosylation is a proapoptotic modification. We conclude that nitrosylation of the heme iron of cytochrome c may be a novel mechanism of apoptosis regulation.
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PMID:Nitrosylation of cytochrome c during apoptosis. 1264 53

We have amplified and characterized partial regions of exons 2 and 3 of the bovine BCL2L1 gene, one of the anti-apoptotic members of the B-cell lymphoma 2 gene family. Cloning and sequencing of the amplified products revealed the existence of several BCL2L1-related sequences, including the bovine BCL2L1 gene and various processed pseudogenes. The bovine BCL2L1 gene revealed two polymorphic nucleotide sequences that resulted in two protein variants, with amino acid replacements at positions 60 and 69. In addition, we report three bovine BCL2L1-related sequences (BCL2L1psi) that probably correspond to intronless processed pseudogenes. These BCL2L1psi pseudogene sequences have accumulated multiple substitutions, deletions and insertions that translated into stop codons or changed the open reading frame of the functional gene. We provide evidence suggesting that the retro-transposition event that originated these processed pseudogenes took place before the divergence of the Cervidae and Bovidae families.
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PMID:Characterization of the bovine BCL2L1 gene and related pseudogenes. 1468 78

Apoptosis is a process whereby cells die in a controlled manner and it is involved in animal development, tissue homeostasis and a variety of diseases. The B-cell lymphoma 2 family proteins are central regulators of intracellular apoptotic signalling cascades. This work describes the isolation of cDNA and genomic fragments from five sheep BCL2 related genes: BCL2, BCL2L1, BCL2L2, BAX and MCL1. Transcript sequences showed a high homology with BCL2 related genes from other species. Three cattle BAC probes containing the homologous BCL2, BCL2L1 and BCL2L2 genes were identified and used for comparative FISH mapping in sheep. BCL2 was localised in OAR23q27, BCL2L1 in OAR13q22 and BCL2L2 in OAR7q15-->q21. Intron polymorphisms were used for linkage mapping of BAX and MCL1, which were mapped on OAR14 and OAR1 respectively. Moreover, a BCL2L1 pseudogene was also identified and linkage mapped on OAR2. The expression of these genes was analysed in mammary gland, ovary, intestine and brain which are target tissues for sheep pathological processes where apoptosis is involved.
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PMID:Positional and functional characterisation of apoptosis related genes belonging to the BCL2 family in sheep. 1590 48

Most of the current medical treatments for endometriosis aim to downregulate estrogen activity. However, a high recurrence rate after medical treatment has been the most significant problem. BAY 11-7085, a soluble inhibitor of NK-kappaB activation, has been shown to inhibit cell proliferation and induce apoptosis of a variety of cells. To examine the potential application of BAY 11-7085 in the treatment of endometriosis, we investigated the effects of this agent on the cell proliferation and apoptosis of cultured ovarian endometriotic cyst stromal cells (ECSCs) by a modified methylthiazole tetrazolium assay, a 5-bromo-2'-deoxyuridine incorporation assay, and internucleosomal DNA fragmentation assays. The effect of BAY 11-7085 on the cell cycle of ECSCs was also determined by flow cytometry. The expression of apoptosis-related molecules was examined in ECSCs with Western blot analysis. BAY 11-7085 significantly inhibited the cell proliferation and DNA synthesis of ECSCs and induced apoptosis and the G0/G1 phase cell cycle arrest of these cells. Additionally, downregulation of the B-cell lymphoma/leukemia-2 (Bcl-2) and Bcl-X(L) expression with simultaneous activation of caspase-3, -8, and -9 was observed in ECSCs after treatment with BAY 11-7085. These results suggest that BAY 11-7085 induces apoptosis of ECSCs by suppressing antiapoptotic proteins, and that caspase-3-, -8-, and -9-mediated cascades are involved in this mechanism. Therefore, BAY 11-7085 could be used as a therapeutic agent for the treatment of endometriosis.
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PMID:Application of the nuclear factor-kappaB inhibitor BAY 11-7085 for the treatment of endometriosis: an in vitro study. 1689 68

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma resistant to conventional chemotherapy. The Bcl-2 pathway is deregulated in these tumors and may represent an interesting target for new therapeutic strategies. The new small-molecule pan-Bcl-2 inhibitor GX15-070 mimics BH3-only proteins by binding to multiple antiapoptotic Bcl-2 members. Here we show that GX15-070 induced apoptosis in vitro in MCL cell lines and primary cells from patients with MCL by releasing Bak from Mcl-1 and Bcl-X(L) at short incubation times and low micromolar doses. GX15-070 was effective in cells bearing defective DNA damage-sensor genes or cell-cycle regulators, inducing Bax and Bak conformational changes, mitochondrial depolarization, phosphatidylserine exposure, and caspase-3 activation. Furthermore, GX15-070 synergized with bortezomib, sensitizing MCL cells to low doses of this proteasome inhibitor, by neutralizing bortezomib-induced Mcl-1 accumulation and cooperating with Noxa to induce Bak displacement from this protein. These events led to an increased activation of the mitochondrial apoptotic pathway. Importantly, GX15-070 alone or in combination with bortezomib showed no significant cytotoxic effect in peripheral blood mononuclear cells from healthy donors. All these findings suggest that GX15-070 alone or in combination with bortezomib represents a new attractive therapeutic approach for MCL treatment.
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PMID:The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. 1722 35

Lumiliximab is a chimeric macaque-human monoclonal antibody to CD23, a protein expressed on virtually all chronic lymphocytic leukemia (CLL) cells. We examined the ability of lumiliximab to mediate apoptosis, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity against primary CLL cells and CD23-expressing B-cell lines. Our data suggest that lumiliximab kills CLL cells and CD23-expressing B cells predominantly by apoptosis, which occurs through the intrinsic pathway. Lumiliximab-induced apoptosis was accompanied by the down-regulation of antiapoptotic proteins Bcl-2, Bcl-X(L), and XIAP, activation of Bax, and release of cytochrome c from the mitochondria. We also found that the addition of lumiliximab to rituximab or fludarabine results in synergistic cytotoxicity of primary CLL cells and CD23-expressing B-cell lines. We investigated the in vivo activity of lumiliximab in a human disseminated CD23(+) B-cell lymphoma SCID mouse model and found greater antitumor activity with it than with control antibody. We also found that paralysis-free survival was greater with lumiliximab plus rituximab or fludarabine than with any of those agents alone. These results suggest that lumiliximab may be an effective treatment alone or in combination with rituximab or chemotherapy agents in CLL or other CD23-overexpressing B-cell malignancies.
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PMID:Mediation of apoptosis by and antitumor activity of lumiliximab in chronic lymphocytic leukemia cells and CD23+ lymphoma cell lines. 1803 10

Although the ultimate outcome of prolonged exposure of cells to stress is often death, the early response appears to be the activation of survival pathways that are likely to give the cell an opportunity to repair low-level damage. How these stress-initiated survival pathways influence B cell lymphoma/leukemia 2 (Bcl-2) proteins, the core cell death machinery, has remained unclear; however, two papers now provide insight into stress-mediated survival mechanisms. The liver is unusually resistant to p53-mediated apoptosis. It appears that p53-mediated induction of the gene that encodes insulin-like growth factor-binding protein-1 (IGFBP1) attenuates the cell death response in hepatocytes by preventing the formation of a complex between p53 and the proapoptotic protein BAK. This is especially interesting as IGFBP1 is not a member of the Bcl-2 family, yet it inhibited BAK. In three unrelated cell lines, another regulatory interaction that influences cell survival occurs at the mitochondria. In this case, protein phosphatase 1gamma (PP1gamma) regulated the phosphorylation status of the Bcl-2/Bcl-X(L)-associated death promoter (BAD). The prefoldin family member URI is normally phosphorylated by S6 kinase 1, which liberates PP1gamma from a URI-PP1gamma complex. However, the withdrawal of growth factors or nutrients stabilizes this complex, which renders PP1gamma inactive. The net response of this stress stimulus is an increased abundance of phosphorylated BAD, which raises the threshold required to trigger cell death. These two studies have identified new players and mechanisms that integrate stress responses and cell death.
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PMID:Cell stress gives a red light to the mitochondrial cell death pathway. 1828 8

Overexpression of antiapoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying antiapoptotic function can potentially overcome this in-trinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of antiapoptotic Bcl-2 family members including Bcl-2, Bcl-X(L), and Mcl-1. In vitro, AT-101 exhibits concentration- and time-dependent cytotoxicity against lymphoma and multiple myeloma cell lines, enhancing the activity of cytotoxic agents. The IC(50) for AT-101 is between 1 and 10 microM for a diverse panel of B-cell lymphomas. AT-101 was synergistic with carfilzomib (C), etoposide (E), doxorubicin (D), and 4-hydroxycyclophosphamide (4-HC) in mantle cell lymphoma (MCL) lines. In a transformed large B-cell lymphoma line (RL), AT-101 was synergistic when sequentially combined with 4-HC, but not when both drugs were added simultaneously. AT-101 also induced potent mitochondrial membrane depolarization (Delta Psi m) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In severe combined immunodeficient (SCID) beige mouse models of drug-resistant B-cell lymphoma, 35 mg/kg per day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide (Cy) and rituximab (R) in a schedule-dependent manner enhanced the efficacy of the conventional therapy.
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PMID:Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma. 1850 36


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