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)

In this study we use the N-substituted benzamides declopramide (3-CPA) and N-acetyl declopramide (Na-3-CPA) to investigate the involvement of the transcription factor NF-kappaB in the induction of apoptosis and surface immunoglobulin kappa (Igkappa) expression in the mouse pre-B cell line 70Z/3. We first showed that 3-CPA-induced apoptosis at doses around 500 microM and that the 3-CPA-induced apoptosis could be suppressed by over-expression of the Bcl-2 protein. Na-3-CPA was shown to be non-apoptotic at doses up to 1-2 mM. On the other hand, Na-3-CPA inhibited LPS-induced Igkappa expression while 3-CPA had no effect. Further analysis showed that while 3-CPA inhibited breakdown of IkappaBalpha, Na-3-CPA inhibited breakdown of IkappaBbeta. In addition, we used a 70Z/3 cell line expressing a dominant negative IkappaBalpha (70Z/3(deltaNIkappaBalpha)). The 70Z/3(deltaNIkappaBalpha) cell line was shown to be more sensitive to apoptosis and cytotoxicity induced by 3-CPA as well as by LPS, probably due to a defect in NF-kappaB rescue mechanism. Taken together, our data implicate distinct roles for IkappaBalpha and IkappaBbeta in regulating various NF-kappaB activities.
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PMID:Differential usage of IkappaBalpha and IkappaBbeta in regulation of apoptosis versus gene expression. 1253 63

A set of signals separate from those needed for T cell activation and clonal expansion acts to sustain a T cell response once it has begun. Immunologic adjuvants can initiate these signals in a process we designate adjuvant-induced survival (AIS). Here, the natural adjuvant LPS was used in a super-antigen model of AIS to understand which factors are needed to sustain T cell survival after activation. Flow cytometric stains for antiapoptotic Bcl-2 and Bcl-xL showed that neither factor was well correlated with AIS, although both were increased transiently upon T cell activation. T cells protected via AIS showed no increased ability to resist death caused by reactive oxygen species, and cellular division was not accelerated as might be expected if AIS were to operate through co-stimulatory pathways. Finally, microarray analyses were performed that showed increased expression of Bcl-3, an NFkappaB/IkappaB factor, was correlated with AIS. It is proposed that T cell survival during productive immune responses occurs by successive activities of Bcl-2, Bcl-xL and Bcl-3, with Bcl-3 requiring innate immune responses to adjuvants for its expression.
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PMID:Stronger correlation of bcl-3 than bcl-2, bcl-xL, costimulation, or antioxidants with adjuvant-induced T cell survival. 1253 59

Cytokines play an important role in regulating the development and homeostasis of B cells by controlling their viability. In this study, we show that the recently described T cell-derived cytokine IL-21 induces the apoptosis of resting primary murine B cells. In addition, the activation of primary B cells with IL-4, LPS, or anti-CD40 Ab does not prevent IL-21-mediated apoptosis. The induction of apoptosis by IL-21 correlates with a down-regulation in the expression of Bcl-2 and Bcl-x(L), two antiapoptotic members of the Bcl-2 family. Furthermore, the reconstitution of Bcl-x(L) or Bcl-2 expression protects primary B cells from IL-21-induced apoptosis. In addition, a short-term preactivation of B cells with anti-CD40 Ab confers protection from IL-21-mediated apoptosis through the up-regulation of Bcl-x(L). These studies reveal a novel pathway that mediates B cell apoptosis via the IL-21R and suggest that IL-21 may play a role in regulating B cell homeostasis.
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PMID:IL-21 induces the apoptosis of resting and activated primary B cells. 1268 41

Our previous studies show that Bcl-2, a regulator of apoptosis, may be involved in the reduction of mucous cell metaplasia (MCM) during recovery from inflammatory responses. The present study was to determine whether neutrophilic inflammation mediates Bcl-2 expression in mucous cells. Rats were intratracheally instilled with 50-1000 microg of LPS. The number of neutrophils recovered by bronchoalveolar lavage (BAL) increased with the dose of LPS, and the percentage of Bcl-2-expressing cells increased with the numbers of neutrophils in the BAL. Depletion of neutrophils did not reduce MCM, but the percentage of Bcl-2-positive cells increased 1.8-fold in neutrophil-depleted compared with controls. Injection of rats with bezafibrate, an inducer of cytochrome P-450, doubled the number of neutrophils in the BAL, decreased MCM twofold compared with vehicle-injected controls, and reduced Bcl-2 expression. Bcl-2 mRNA levels decreased in a tracheal epithelial cell line treated with bezafibrate. These data demonstrate that Bcl-2 expression is independent of the number of neutrophils in the BAL and that bezafibrate may directly reduce Bcl-2 expression in epithelial cells.
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PMID:LPS-induced neutrophilic inflammation and Bcl-2 expression in metaplastic mucous cells. 1270 18

C-Phycocyanin (C-PC) is one of the major biliproteins of Spirulina platensis, a blue green algae, with antioxidant and radical scavenging properties. It is also known to exhibit anti-inflammatory and anti-cancer properties. However, the mechanism of action of C-PC is not clearly understood. Previously, we have shown that C-PC selectively inhibits cyclooxygenase-2 (COX-2), an inducible isoform that is upregulated during inflammation and cancer. In view of the reported induction of apoptosis in cancer cells by cyclooxygenase-2 inhibitors, the present study is undertaken to test the effect of C-PC on LPS stimulated RAW 264.7 mouse macrophage cell line. These studies have shown a dose dependent reduction in the growth and multiplication of macrophage cell line by C-PC. This decrease in cell number appears to be mediated by C-PC induced apoptosis as evidenced by flow cytometric and confocal microscopic studies. Cells treated with 20 micro M C-PC showed typical nuclear condensation and 16.6% of cells in sub-G(o)/G(1) phase. These cells also showed DNA fragmentation in a dose dependent manner. The studies on poly(ADP ribose) polymerase (PARP) cleavage showed typical fragmentation pattern in C-PC treated cells. This C-PC induced apoptosis in RAW 264.7 cells appears to be mediated by the release of cytochrome c from mitochondria and independent of Bcl-2 expression. These effects of C-PC on RAW 264.7 cells may be due to reduced PGE(2) levels as a result of COX-2 inhibition.
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PMID:C-Phycocyanin, a selective cyclooxygenase-2 inhibitor, induces apoptosis in lipopolysaccharide-stimulated RAW 264.7 macrophages. 1271 27

Nuclear transcription factor kappa B (NF-kappaB) has been shown both to block apoptosis and to promote cell proliferation, and hence has been considered an important target for anticancer drug development. The pyrimidine analogue cytosine arabinoside (araC) is among the most effective agents used in the treatment of acute leukemia, and we demonstrate in this study that its chemotherapeutic activity may be mediated by its inhibition of NF-kappaB. We found that in Jurkat cells, although tumor necrosis factor (TNF), araC, or ceramide induced NF-kappaB, the induction was only transient in the case of araC. In both HuT-78 and serum-activated LPS-stimulated Jurkat (SA-LPS/Jkt) cells that expressed NF-kappaB, TNF or ceramide treatments did not affect the NF-kappaB expression whereas araC downregulated it. AraC, but not TNF or ceramide was able to induce apoptosis in these cells as detected by assays for lipid peroxidation, reactive oxygen intermediates generation, caspase activation, cytotoxicity, Bcl-2 degradation, and DNA fragmentation. AraC also potentiated apoptosis mediated by cis-platin, etoposide, or taxol in these cells. AraC was able to induce protein phosphatases (PP) 2A and 2B-A, and phosphorylation of p65 subunit of NF-kappaB in the HuT-78 and SA-LPS/Jkt cells was downregulated by araC treatment. Furthermore, calyculin A, a specific phospho-serine/phospho-threonine phosphatase inhibitor, protected HuT-78 and SA-LPS/Jkt cells from araC-mediated NF-kappaB downregulation and apoptosis. These observations collectively suggest that araC induces apoptosis in NF-kappaB-expressing cells by dephosphorylating the p65 subunit of NF-kappaB.
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PMID:Mechanism of cytosine arabinoside-mediated apoptosis: role of Rel A (p65) dephosphorylation. 1285 72

Exposure of pulmonary airways to environmental toxins and allergens may cause proliferation of airway epithelial cells and mucous cell metaplasia (MCM); however, it is unclear to what extent proliferating cells differentiate into mucus-storing cells and contribute to MCM. Our previous studies demonstrated that Bcl-2, an inhibitor of apoptosis with cell cycle regulatory functions, is expressed in metaplastic mucous cells. The purpose of the present study was to investigate the number of metaplastic mucous cells that are derived from proliferating epithelial cells and whether Bcl-2 has a role in cell cycle entry in these cells. Rats were intratracheally instilled with 100 microg of LPS from Pseudomonas aeruginosa in 500 microl of saline, and proliferating airway cells were labeled with bromodeoxyuridine (BrdU) by implanting a subcutaneous osmotic pump 24 h before instillation. The volume of stored mucosubstance and the number of mucous cells were increased 10- and 3-fold, respectively, from 24-48 h after instillation. The number of total epithelial cells per millimeter of basal lamina increased, and the number of serous cells per millimeter of basal lamina decreased during this time. Approximately 50% of Alcian blue-periodic acid Schiff-stained mucous cells were labeled with BrdU at 48 h after instillation, suggesting that one-half of the secretory cells were derived from proliferating cells. Furthermore, 50% of the Bcl-2-positive mucous cells were BrdU negative and therefore derived from nonproliferating, preexisting cells. Our findings demonstrate that preexisting and proliferating cells differentiate into mucous cells and compose LPS-induced metaplasia and that Bcl-2 does not have cell cycle regulatory function in these cells.
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PMID:DNA synthesis and Bcl-2 expression during development of mucous cell metaplasia in airway epithelium of rats exposed to LPS. 1452 29

Gut epithelial apoptosis is increased in human studies and animal models of noninfectious inflammation and sepsis. Elevated intestinal cell death appears to be physiologically significant in sepsis. Previous studies demonstrate that overexpression of the antiapoptotic protein Bcl-2 in the gut epithelium of transgenic mice is associated with improved survival from Pseudomonas aeruginosa pneumonia and cecal ligation and puncture. The functional significance of elevated gut apoptosis in noninfectious inflammation has not been examined. We hypothesized that intestinal apoptosis would be detrimental to survival in noninfectious critical illness. To address this issue, acute lung injury (ALI) was induced with intratracheal injection of lipopolysaccharide (LPS, 800 microg) in wild-type (WT) FVB/N mice and transgenic mice that overexpress Bcl-2 in their intestinal epithelium. Guts were harvested at 12, 24, 48, and 72 h and assessed for apoptosis by both hematoxylin and eosin and active caspase-3 staining in 100 contiguous crypts. ALI increased gut epithelial apoptosis 12 h after LPS instillation compared with shams (P < 0.01), whereas overexpression of Bcl-2 decreased intestinal apoptosis compared with WT animals with ALI when assayed by active caspase-3 (P < 0.05). Plasma levels of tumor necrosis factor alpha, interleukin (IL)-6, and IL-10 were similar between WT and transgenic animals with ALI, both of which had elevated IL-10 levels at 12 h and elevated IL-6 levels at 24 h compared with sham animals. In a separate experiment, transgenic and WT animals with ALI were followed for mortality to determine whether gut overexpression of Bcl-2 conferred a survival advantage. Survival at 10 days was 73% in WT animals (n = 33) and 65% in Bcl-2 animals (n = 23, P = ns). These results indicate that while gut epithelial apoptosis is elevated in multiple models of critical illness, prevention of intestinal cell death by overexpression of Bcl-2 is associated with a disparate survival effect between sepsis and noninfectious inflammation.
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PMID:Bcl-2 inhibits gut epithelial apoptosis induced by acute lung injury in mice but has no effect on survival. 1456 Jan 8

In our search for NF-kappaB inhibitors from natural resources, we have previously identified two structurally related dilignans, manassantin A and B as specific inhibitors of NF-kappaB activation from Saururus chinensis. However, their molecular mechanism of action remains unclear. We here demonstrate that manassantins A and B are potent inhibitors of NF-kappaB activation by the suppression of transciptional activity of RelA/p65 subunit of NF-kappaB. These compounds significantly inhibited the induced expression of NF-kappaB reporter gene by LPS or TNF-alpha in a dose-dependent manner. However, these compounds did not prevent the DNA-binding activity of NF-kappaB assessed by electrophoretic mobility shift assay as well as the induced-degradation of IkappaB-alpha protein by LPS or TNF-alpha. Further analysis revealed that manassantins A and B dose-dependently suppressed not only the induced NF-kappaB activation by overexpression of RelA/p65, but also transactivation activity of RelA/p65. Furthermore, treatment of cells with these compounds prevented the TNF-alpha-induced expression of anti-apoptotic NF-kappaB target genes Bfl-1/A1, a prosurvival Bcl-2 homologue, and resulted in sensitizing HT-1080 cells to TNF-alpha-induced cell death. Similarly, these compounds also suppressed the LPS-induced inducible nitric oxide synthase expression and nitric oxide production. Taken together, manassantins A and B could be valuable candidate for the intervention of NF-kappaB-dependent pathological condition such as inflammation and cancer.
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PMID:Suppression of RelA/p65 transactivation activity by a lignoid manassantin isolated from Saururus chinensis. 1459 50

Tumor necrosis factor (TNF) is a pleiotropic cytokine that potentiates the cytotoxic effects of chemotherapeutic drugs. Although emergence of resistance to chemotherapeutic drugs is a major problem in cancer therapy, its mechanism is incompletely understood. Recently, activation of a nuclear transcription factor NF-kappa B has been reported to be a signal for anti-apoptosis. In this report, we investigated the effect of TNF on activation of NF-kappa B, c-Jun N-terminal kinase (JNK), and apoptosis in vincristine-resistant human histiocytic lymphoma U937-VR cells. Unlike the parent clone (U937-VS), no activation of caspase-3, known to be required for apoptosism was found in vincristine-resistant cells on exposure to vincristine. These cells were also more resistant than U-937-VS cells to doxorubicin, daunomycin, and taxol. TNF-induced NF-kappa B activation, I kappa B alpha degradation, and nuclear translocation of p65 were all found to be highly suppressed in the U-937-VR cells. NF-kappa B activation by LPS, H2O2, and okadaic acid was also suppressed. However, vincristine resistance enhanced TNF-induced JNK activation. When examined for apoptosis, vincristine resistance suppressed the cytotoxic effects and caspase-3 activation by TNF. The resistant phenotype in U937-VR cells was independent of the expression of the apoptosis-suppressor, Bcl-2. Thus, overall these results indicate that vincristine resistance correlates with suppression of NF-kappa B activation, cytotoxicity, and caspase-3 activation but enhancement of JNK activation by TNF.
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PMID:Cellular resistance to vincristine suppresses NF-kappa B activation and apoptosis but enhances c-Jun-NH2-terminal protein kinase activation by tumor necrosis. 1469


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