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)

Emerging data indicate that growth factors such as insulin-like growth factor-1 (IGF-1) prevent neuronal death due to nitric oxide (NO) toxicity. On the other hand, growth factors can promote cell survival by acting on phosphatidylinositol 3-kinase (PI3-kinase) and its downstream target, serine-threonine kinase Akt, in various types of cells. Here, we examined the mechanism by which IGF-1 inhibits neuronal apoptosis induced by NO in primary hippocampal neurons. IGF-1 was capable of preventing apoptosis and caspase-3-like activation induced by a NO donor, sodium nitroprusside or 3-morpholin-osydnonimine. Incubation of neurons with a P13-kinase inhibitor, wortmannin or LY294002, blocked the effects of IGF-1 on NO-induced neurotoxicity and caspase-3-like activation. In addition, the P13-kinase inhibitors blocked the effect of IGF-1 on down-regulation in Bcl-2 and upregulation in Bax expression induced by NO. Adenovirus-mediated overexpression of the activated form of Akt significantly inhibited NO-induced cell death, caspase-3-like activation, and changes in Bcl-2 and Bax expression. Moreover, expression of the kinase-defective form of Akt almost completely blocked the effects of IGF-1. These findings suggest that activation of Akt is necessary and sufficient for the effect of IGF-1 and is capable of preventing NO-induced apoptosis by modulating the NO-induced changes in Bcl-2 and Bax expression.
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PMID:Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. 1053 63

The histone deacetylase inhibitor and potential anti-cancer drug sodium butyrate is a general inducer of growth arrest, differentiation, and in certain cell types, apoptosis. In human CCRF-CEM, acute T lymphoblastic leukemia cells, butyrate, and other histone deacetylase inhibitors caused G2/M cell cycle arrest as well as apoptotic cell death. Forced G0/G1 arrest by tetracycline-regulated expression of transgenic p16/INK4A protected the cells from butyrate-induced cell death without affecting the extent of histone hyperacetylation, suggesting that the latter may be necessary, but not sufficient, for cell death induction. Nuclear apoptosis, but not G2/M arrest, was delayed but not prevented by the tripeptide broad-range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp.fluoromethylketone (zVAD) and, to a lesser extent, by the tetrapeptide 'effector caspase' inhibitors benzyloxycarbonyl-Asp-Glu-Val-Asp.fluoromethylketone (DEVD) and benzyloxycarbonyl-Val-Glu-Ile-Asp.fluoromethyl-ketone (VEID); however, the viral protein inhibitor of 'inducer caspases', crmA, had no effect. Bcl-2 overexpression partially protected stably transfected CCRF-CEM sublines from butyrate-induced apoptosis, but showed no effect on butyrate-induced growth inhibition, further distinguishing these two butyrate effects. c-myc, constitutively expressed in CCRF-CEM cells, was down-regulated by butyrate, but this was not causative for cell death. On the contrary, tetracycline-induced transgenic c-myc sensitized stably transfected CCRF-CEM derivatives to butyrate-induced cell death.
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PMID:Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts. 1054 82

This study deals with the apoptotic effect exerted on human retinoblastoma Y79 cells by both sodium butyrate and an inhibitor of 26S proteasome [z-Leu-Leu-Leu-CHO (MG132)] and their synergistic effect. Exposure to sodium butyrate (1-4 mM) induced an accumulation of cells in the G2-M phase that was already visible after 24 h of treatment, when morphological and biochemical signs of apoptosis appeared only in a small number of cells (5-10%). Thereafter, the apoptotic effects increased progressively with slow kinetics, reaching a maximum after 72 h of exposure, when they concerned a large fraction of cells (>75% with 4 mM sodium butyrate). Sodium butyrate stimulated the conversion of procaspase-3 into caspase-3 and also induced the cleavage of poly-(ADP-ribose) polymerase and lamin B, two hallmarks of apoptosis. All of the apoptotic signals were suppressed by benzyloxy carbonyl-Val-Ala-Asp-fluoromethylketone (a general inhibitor of caspase activities), whereas acetyl-Asp-Glu-Val-Asp aldehyde, a specific inhibitor of caspase-3 activity, only induced a partial reversion of the apoptotic effects. Sodium butyrate also decreased the Bcl-2 level, whereas it increased the Bax level and stimulated the release of cytochrome c from the mitochondria, an event that was most likely responsible for the activation of caspase-3. Finally, sodium butyrate activated 26S proteasome, the major extralysosomal degradative machinery, which is responsible for the degradation of short-lived proteins. Consequently, the levels of p53, N-myc, and IkappaBalpha (factors that play regulatory roles in apoptosis) diminished, whereas the nuclear level of nuclear factor kappaB concomitantly increased. Treatment of Y79 cells with MG132 induced apoptosis with more rapid kinetics than with sodium butyrate. The effects appeared after 8 h of incubation, reaching a maximum at 24 h, and they were accompanied by increased levels of N-myc, p53, and IkappaBalpha. MG132 also favored the release of cytochrome c from the mitochondria and increased the activity of caspase-3. When Y79 cells were exposed to combinations of sodium butyrate and MG132, the latter compound suppressed the decreasing effect induced by sodium butyrate on the levels of p53, N-myc, and IkappaBalpha and the increasing effect on the nuclear level of nuclear factor kappaB. Moreover, an increase in the level of Bax and an enhancement in the release of cytochrome c from the mitochondria were observed. Clear synergistic effects concerning the activation of both caspase-3 and apoptosis were induced by a combination of suboptimal doses of sodium butyrate and MG132. The results support the conclusion that MG132 potentiates the apoptotic effect of sodium butyrate by suppressing its stimulatory effect on 26S proteasome activity. Synergistic interactions between butyrate and inhibitors of proteasome could represent a new important tool in tumor therapy and, in particular, the treatment of retinoblastoma.
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PMID:The apoptotic effects and synergistic interaction of sodium butyrate and MG132 in human retinoblastoma Y79 cells. 1055 39

In normal epithelial cells, impaired cell-matrix contact leads to induction of programmed cell death, a process that has been termed 'anoikis'. We investigated the role of p53 and other apoptotic proteins in anoikis in thyroid epithelial cells. Western blot analysis demonstrated that neither p53 nor Bcl-2, Bcl-XL and Bax protein expression changed during anoikis. However, loss of endogenous p53 activity in cells transfected with a dominant-negative mutated p53 inhibited anoikis demonstrating the involvement of p53-dependent processes. The phosphatase inhibitor sodium orthovanadate opposed anoikis when added to the cells within 6 h, suggesting a role for phosphorylated proteins.
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PMID:Apoptosis induced by denied adhesion to extracellular matrix (anoikis) in thyroid epithelial cells is p53 dependent but fails to correlate with modulation of p53 expression. 1058 91

Expression of the Bcl-2 family members in a human hepatocellular carcinoma cell line (HCC-T) after sodium butyrate-treatment was investigated. Sodium butyrate, a histone deacetylase inhibitor, induced differentiation of the cell line into its normal counterpart without inducing apoptosis at the concentration of 2 mmol/l. Since sodium butyrate has effects on both differentiation and apoptosis, we investigated the expression profile of bcl-2 related genes in HCC-T. The expression of Bcl-2 and Mcl-1/EAT was up-regulated 4-12 h after the treatment while Bcl-XL was up-regulated 2-3 days after the stimulation. On the other hand, the expression levels of Bax protein remained unchanged during differentiation. The HCC-T cells entered a cell cycle arrest at G1 and showed neither cellular fragmentation nor apoptosis during this period, which was concomitantly associated with up-regulated expression of a cell cycle regulator, p21WAF-1. These results demonstrate that induction of anti-apoptotic bcl-2 related proteins at an early stage of differentiation is important for the maintenance of HCC-T cell differentiation by antagonizing pro-apoptotic molecules such as Bax.
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PMID:Bcl-2 related proteins are dramatically induced at the early stage of differentiation in human liver cancer cells by a histone deacetylase inhibitor projecting an anti-apoptotic role during this period. 1067 72

Adrenomedullin, which was discovered as a vasodilating peptide, has been reported to be produced in various organs, in which adrenomedullin regulates not only vascular tone but also cell proliferation and differentiation in an autocrine/paracrine manner. We evaluated the effect of adrenomedullin on endothelial cell apoptosis. Human umbilical vein endothelial cells underwent apoptosis when cultured in serum-free medium. Treatment with adrenomedullin reduced the number of cells with pyknotic nuclei (Hoechst 33258 staining) and inhibited cell death (dimethylthiazol-diphenyltetrazolium bromide assay) in a dose-dependent manner. The administration of adrenomedullin did not alter the expression levels of Bcl-2 family proteins. Experiments with analogs of cAMP or a cAMP-elevating agonist demonstrated that elevation of the intracellular cAMP concentration does not mediate the antiapoptotic effect of adrenomedullin. The coadministration of N-nitro-L-arginine methyl ester (2 mmol/L), an inhibitor of nitric oxide synthase, abrogated the effect of adrenomedullin. Lower doses of sodium nitroprusside (1 to 10 micromol/L), a nitric oxide donor, mimicked the antiapoptotic effect of adrenomedullin. The antiapoptotic effect of sodium nitroprusside was not attenuated by the inhibition of soluble guanylyl cyclase with 1 micromol/L oxadiazolo-quinoxalin-1-one nor could apoptosis be inhibited by the incubation of human umbilical vein endothelial cells with 1 mmol/L 8-bromo-cGMP, a cell-permeant cGMP analog. These results indicate that adrenomedullin and nitric oxide inhibit endothelial cell apoptosis via a cGMP-independent mechanism.
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PMID:Adrenomedullin and nitric oxide inhibit human endothelial cell apoptosis via a cyclic GMP-independent mechanism. 1090 17

There is increasing evidence suggesting that chondrocyte death may contribute to the progression of osteoarthritis (OA). This study focused on the characterization of signaling cascade during NO-induced cell death in human OA chondrocytes. The NO generator, sodium nitroprusside (SNP), promoted chondrocyte death in association with DNA fragmentation, caspase-3 activation, and down-regulation of Bcl-2. Both caspase-3 inhibitor Z-Asp(OCH3)-Glu(OCH3)-Val-Asp(OCH3)-CH2F and caspase-9 inhibitor Z-Leu-Glu(OCH3)-His-Asp(OCH3)-CH2F prevented the chondrocyte death. Blocking the mitogen-activated protein kinase pathway by the mitogen-activated protein kinase kinase 1/2 inhibitor PD98059 or p38 kinase inhibitor SB202190 also inhibited the SNP-mediated cell death, suggesting possible requirements of both extracellular signal-related protein kinase 1/2 and p38 kinase for the NO-induced cell death. Furthermore, the selective inhibition of cyclooxygenase (COX)-2 by NS-398 or the inhibition of COX-1/COX-2 by indomethacin blocked the SNP-induced cell death. The chondrocyte death induced by SNP was associated with an overexpression of COX-2 protein (as determined by Western blotting) and an increase in PGE2 release. PD98059 and SB202190, but neither Z-DEVD FMK nor Z-LEHD FMK completely inhibited the SNP-mediated PGE2 production. Analysis of interactions between PGE2 and the cell death showed that PGE2 enhanced the SNP-mediated cell death, whereas PGE2 alone did not induce the chondrocyte death. These data indicate that NO-induced chondrocyte death signaling includes PGE2 production via COX-2 induction and suggest that both extracellular signal-related protein kinase 1/2 and p38 kinase pathways are upstream signaling of the PGE2 production. The results also demonstrate that exogenous PGE2 may sensitize human OA chondrocytes to the cell death induced by NO.
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PMID:The induction of cell death in human osteoarthritis chondrocytes by nitric oxide is related to the production of prostaglandin E2 via the induction of cyclooxygenase-2. 1097 59

This paper studies the effects caused in human retinoblastoma Y79 cells by treatment with combinations of sodium butyrate, the inhibitor of topoisomerase I camptothecin and the inhibitor of 26S proteasome MG132. The combination of sodium butyrate and camptothecin resulted in a strong synergistic cytotoxicity, as revealed by combination indices of 0.77 and 0.52 calculated at IC(50) and IC(75). Synergistic interactions were also demonstrated for combinations of sodium butyrate and MG132, camptothecin and MG132 and for a combination of all three compounds. The cytotoxic effects observed after the combined treatments can be considered a consequence of apoptosis, as suggested by the appearance of morphological signals of apoptosis and by the activation of caspase-3 with degradation of poly-ADP ribose polymerase and lamin B. Treatment of Y79 cells with sodium butyrate alone lowered the levels of p53, E2F-1 and Bcl-2. The addition of MG132 to sodium butyrate counteracted the effect on p53 only, while the addition of camptothecin to sodium butyrate counteracted the effect on both p53 and E2F-1. The treatment of Y79 cells with the triple combination increased the level of p53, decreased that of Bcl-2, while the level of E2F-1 was not modified. We suggest that the effects exerted on the levels of these regulatory proteins can explain the synergistic interactions demonstrated between sodium butyrate, camptothecin and MG132.
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PMID:Synergistic cytotoxic interactions between sodium butyrate, MG132 and camptothecin in human retinoblastoma Y79 cells. 1100 74

The present study was aimed at evaluating the effect of high intracolonic butyrate concentrations, either through fermentation of a soluble fiber-enriched diet or via intracolonic butyrate instillation, on colon cancer in a chemically induced (dimethylhydrazine) rat model. The effects were tested in four groups of dimethylhydrazine-treated rats: (i) rats fed a standard diet, (ii) rats fed a diet enriched with 15% citrus pectin, a soluble fiber that ferments and produces a high concentration of intracolonic butyrate, (iii) rats fed a standard diet and intrarectally instilled with a sodium butyrate solution (50 mM), (iv) rats fed a standard diet and intrarectally instilled with sodium butyrate vehicle solution (100 mM NaCl). The apoptotic index in the distal colon of rats fed pectin was higher than in colonic tissue from rats fed a standard diet. The expression of caspase-1, a cysteine protease implicated in the regulation of programmed cell death, as detected by both Northern and Western analysis, showed the highest mRNA and protein levels in colonic tissue from rats intrarectally instilled with butyrate. Immunohistology confirmed the Western blot findings. Expression of the cleaved poly(ADP-ribose) polymerase product, a downstream nuclear substrate for caspase-3 in the apoptotic pathway, was elevated in both the pectin-fed and butyrate-instilled groups. Expression of the antiapoptotic protein Bcl-2 was significantly reduced following pectin feeding as well as butyrate instillation. The highest expression of Bcl-2 was observed in tumor tissue. A marked reduction in aberrant crypt number was observed in colonic tissue obtained from both the pectin-fed and butyrate-instilled groups relative to rats from the standard diet group. The average tumor volume per rat in both the pectin-fed and butyrate-instilled groups was significantly lower than in rats from the standard diet and the sodium butyrate vehicle-instilled groups. We conclude that high butyrate levels, either instilled or obtained following fermentation of soluble dietary fibers, inhibit early and late events in colon tumorigenesis by controlling the transcription expression and activity of key proteins involved in the apoptotic cascade.
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PMID:Apoptosis cascade proteins are regulated in vivo by high intracolonic butyrate concentration: correlation with colon cancer inhibition. 1113 27

We previously reported that concanamycin A, a specific inhibitor of vacuolar type H+-ATPases, induces DNA fragmentation in B cell hybridoma HS-72 cells. In the present study, we found that the cytosol from concanamycin A-treated HS-72 cells had a cytotoxic effect on intact cells in a cell viability assay. While activin A also induced apoptosis in HS-72 cells, the cytosol from activin A-treated HS-72 cells had no effect on cell viability. We purified the cytosol from concanamycin A-treated HS-72 cells by a four-step procedure: ultracentrifugation; HiTrap heparin column chromatography; HiTrap Q column chromatography; and reverse-phase high performance liquid chromatography on a C18 hydrophobic support. The biologically active fraction, which was used as partially purified cytosol, gave a specific band of protein with a molecular mass of 33 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The mechanism of cell death was examined by observing changes in nuclear morphology, an increase in the proportion of fragmented DNA, and the typical ladder pattern of degraded chromosomal DNA, indicating the induction of apoptosis in cells cultured with the partially purified cytosol. The overexpression of human Bcl-2 suppressed apoptosis, indicating that the cytosol from concanamycin A-treated HS-72 cells induces apoptosis by a Bcl-2-inhibiting mechanism. These findings suggest that concanamycin A, a vacuolar type H+-ATPase inhibitor, produces intracellular apoptosis-inducing factor in B cell hybridoma.
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PMID:Intracellular apoptosis-inducing factor is induced by a vacuolar type H+-ATPase inhibitor in B lineage cells. 1114 15


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