Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biological function of CD30 in the thymus has been only partially elucidated, although recent data indicate that it may be involved in negative selection. Because CD30 is expressed only by a small subpopulation of medullary thymocytes, we generated transgenic (Tg) mice overexpressing CD30 in T lymphocytes to further address its role in T cell development. CD30 Tg mice have normal thymic size with a normal number and subset distribution of thymocytes. In vitro, in the absence of CD30 ligation, thymocytes of CD30 Tg mice have normal survival and responses to apoptotic stimuli such as radiation, dexamethasone, and Fas. However, in contrast to controls, CD30 Tg thymocytes are induced to undergo programmed cell death (PCD) upon cross-linking of CD30, and the simultaneous engagement of TCR and CD30 results in a synergistic increase in thymic PCD. CD30-mediated PCD requires caspase 1 and caspase 3, is not associated with the activation of NF-kappaB or c-Jun, but is totally prevented by Bcl-2. Furthermore, CD30 overexpression enhances the deletion of CD4+/CD8+ thymocytes induced by staphylococcal enterotoxin B superantigen and specific peptide. These findings suggest that CD30 may act as a costimulatory molecule in thymic negative selection.
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PMID:CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway. 1038 16

We investigated whether cell-permeable, synthetic ceramide (C6 ceramide) could induce apoptosis in Fas-resistant Hodgkin's disease (HD)-derived cell lines. Despite strongly expressing the Fas-receptor, two of three HD-derived cell lines were resistant to Fas-mediated apoptosis. This resistance to Fas could not be attributed to differential Fas isoform generation patterns between the Fas-resistant and the Fas-sensitive cell lines. The Fas-resistant cell lines did not demonstrate the presence of Fas exon 8 deletion. Bcl-2 and BclxL levels were comparable between the Fas-resistant and the Fas-sensitive cell lines. C6 ceramide could induce apoptosis in both Fas-resistant cell lines and this was associated with a decrease in BclxL level. Caspase-1, caspase-3, or pan-caspase inhibitors could not prevent ceramide-induced apoptosis. Furthur, ceramide treatment did not lead to cleavage of caspase 3 or poly(ADP-ribose) polymerase, but caused a loss in mitochondrial transmembrane potential which could not be prevented by caspase inhibitors. Thus, we conclude that ceramide-induced apoptosis in Fas-resistant HD cell lines is caspase independent.
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PMID:Ceramide-induced apoptosis in fas-resistant Hodgkin's disease cell lines is caspase independent. 1066 30

This study was designed primarily to assess the localization of apoptosis cascade proteins along the rat colonic crypt and secondarily to test whether the activity and/or localization of these proteins are affected by the enrichment of the diet with the soluble fiber pectin. Expression of apoptosis cascade proteins was assessed in isolated colonocytes harvested from the luminal and basal crypt colonocyte populations. Two different dietary regimens were tested: a standard diet (diet A), and a diet enriched in pectin (diet B), a soluble fiber that undergoes fermentation in the cecum and produces high concentrations of intracolonic short-chain fatty acids. Caspase-1 expression was maximal in luminal colonocytes of rats fed diet B, as evidenced by Western blot and immunohistological analyses. Expression of the cleaved poly(ADP-ribose) polymerase product was elevated in both the luminal and basal colonocytes of the pectin-fed group, whereas in rats fed diet A, the expression was lower, especially in basal crypt colonocytes. The highest expression of the antiapoptotic protein Bcl-2 was observed in the lower compartments of the colonic crypt tissue and was maximal in the rat group fed a standard diet. The apoptotic index in colonocytes of rats fed diet B was higher than that measured in rats fed diet A. Cumulatively, our results indicate that apoptosis cascade proteins are differentially localized along the lumen-crypt axis, and their expression and activity may be controlled by dietary components. These results may, at least partially, account for the documented protective effect of butyrogenic fibers on colorectal cancer.
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PMID:Dietary regulation and localization of apoptosis cascade proteins in the colonic crypt. 1067 13

Fas (CD95/APO-1) is a cell surface "death receptor" that mediates apoptosis upon engagement by its ligand, FasL. Fas-mediated apoptosis of lymphocytes normally serves immunoregulatory roles, including tolerance acquisition, immune response termination, and maintenance of immune privilege in certain organs. Colon tumors can exploit this lymphocyte death program by expressing FasL. This may enable colon tumors to mount a "Fas counterattack" against antitumor lymphocytes, impairing antitumor immune responses. FasL-expressing colon tumor-derived cell lines can trigger Fas-mediated apoptosis of cocultured T cells in vitro. FasL expressed in esophageal cancer has been significantly associated with apoptosis and depletion of tumor-infiltrating lymphocytes (TIL) in vivo. FasL may also facilitate metastatic colonization of Fas-sensitive organs such as the liver, by inducing apoptosis of target organ cells. Normal colonic epithelial cells express Fas and are relatively sensitive to Fas-mediated apoptosis. By contrast, colon tumor-derived cell lines are usually resistant to induction of Fas-mediated apoptosis, and colon cancer cells frequently coexpress Fas and FasL. The mechanisms allowing resistance to Fas-mediated apoptosis are complex, and defects have been identified at several levels of Fas signal transduction. The "Bcl-2 rheostat" may be pitched against apoptosis in colon cancer, inasmuch as overexpression of Bcl-2, downregulation of Bak, and mutation of Bax are common defects in colon tumors. Caspase-1 is also downregulated in colon cancer. The high frequency of p53 mutations in late-stage cancers may also inhibit Fas signaling. Fundamental defects in apoptosis signaling may contribute to both immuno- and chemoresistance in colon cancer and allow expression of FasL to counterattack antitumor lymphocytes.
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PMID:Altered mechanisms of apoptosis in colon cancer: Fas resistance and counterattack in the tumor-immune conflict. 1091 13

In previous studies, we showed that basic fibroblast growth factor (bFGF) reduced infarct volume when infused intravenously in animal models of focal cerebral ischemia. In the current study, we examined the potential mechanism of infarct reduction by bFGF, especially effects on apoptosis within the ischemic brain. We found that bFGF decreased DNA fragmentation in the ischemic hemisphere, as assessed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) histochemical methods combined with morphological criteria. bFGF also prevented reduction of immunoreactivity of the anti-apoptotic protein Bcl-2 in the ischemic hemisphere, but did not alter immunoreactivity of the pro-apoptotic proteins Bax, Caspase-1, or Caspase-3. These changes in TUNEL histochemistry and Bcl-2 immunoreactivity were especially prominent in cortex at the borders ('penumbra') of infarcts, spared by bFGF treatment. We conclude that the infarct-reducing effects of bFGF may be due, in part, to prevention of downregulation of Bcl-2 expression and decreased apoptosis in the ischemic brain.
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PMID:Intravenous basic fibroblast growth factor (bFGF) decreases DNA fragmentation and prevents downregulation of Bcl-2 expression in the ischemic brain following middle cerebral artery occlusion in rats. 1122 61

Activation of the transcription factor nuclear factor-kappa B (NF-kappa B) has been found to play an essential role in the inhibition of tumor necrosis factor (TNF)-mediated apoptosis. NF-kappa B regulates several antiapoptotic molecules including inhibitors of apoptosis, Bcl-2 family proteins (A1 and Bcl-X(L))(,) and IEX-IL. Here we report that the expression of a small death effector domain (DED)-containing protein, NDED (NF-kappa B-inducible DED-containing protein), depends on the activation of NF-kappa B. The inhibition of NF-kappa B by I kappa B alpha, a natural inhibitor of NF-kappa B, suppressed NDED mRNA expression induced by TNF. The restoration of NDED in NF-kappa B null cells inhibited TNF-induced apoptosis. Intriguingly, unlike the caspase-8 inhibitor cellular FADD-like interleukin-1 beta converting enzyme-inhibitory protein (c-FLIP), NDED suppressed TNF-mediated apoptosis by inhibiting TNF-induced caspase-8 enzymatic activity but not the processing of caspase-8. Furthermore, NDED could not inhibit etoposide-mediated apoptosis that is independent of caspase-8 activation. Our results provide the first demonstration that NF-kappa B transcriptionally induces the DED-containing protein to suppress TNF-mediated apoptosis by inhibiting caspase-8 activity, which offers new insight into the antiapoptotic mechanism of NF-kappa B.
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PMID:Nuclear factor-kappa B-inducible death effector domain-containing protein suppresses tumor necrosis factor-mediated apoptosis by inhibiting caspase-8 activity. 1134 52

The repair of damaged gastric mucosa is a complex process involving prostaglandins (PG) and mucosal growth factors such as epidermal growth factor (EGF). Recently, we postulated that the increased occurrence of apoptosis in the gastric epithelium might be of pathophysiological importance in the development of stress lesions. The aim of the present study was to assess the effect of the pretreatment of rats, exposed to 3.5 h of water immersion and restraint stress (WRS), with EGF and PG (16,16 dmPGE(2)) on the number of stress lesions, recovery of gastric mucosa from stress and the expression of apoptosis related genes such as caspase-3 and antiapoptotic bcl-2. Rats were divided in following groups: (1) vehicle; (2) EGF 100 microg/kg i.p.; (3) 16,16 dm-PGE(2) (5 microg/kg i.g.) and caspase-1 inhibitor (ICE-I; 100 microg/kg i.p.). One hour later, the rats were exposed to 3.5 h of WRS and then sacrificed immediately (0 h) or at 6, 12, or 24 h after WRS. The number of acute gastric lesions was determined. Gastric epithelial apoptosis was assessed by TUNEL staining. In addition, mRNA expression of caspase-3, Bcl-2 and proinflammatory cytokines (IL-1 beta, TNFalpha) was assessed by RT-PCR. PGE(2) generation in gastric mucosa and luminal EGF were determined by RIA. Exposure to WRS resulted in the development of multiple acute stress erosions ( approximately 18) which almost completely healed during 24 h. The gastric blood flow was significantly reduced (approximately 70% of intact mucosa) immediately after WRS. The expression of mRNA for IL-1 beta and TNF alpha reached their peak at 12 h after stress exposure. The apoptosis rate was highest at 6 h after WRS and was accompanied by the highest caspase-3 expression. In rats pretreated with EGF or 16,16 dm-PGE(2), a significant decrease in caspase-3 mRNA and upregulation of bcl-2 mRNA as observed as compared to vehicle controls. Caspase-1 inhibitor significantly reduced the number of stress lesions. We conclude that EGF and PGE(2) accelerate healing of stress-induced lesions due to the attenuation of apoptosis via upregulation of bcl-2 in gastric mucosa. Inhibitors of apoptosis accelerate healing of stress lesions and may be potentially effective agents in the healing of damaged gastric mucosa.
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PMID:Epidermal growth factor and prostaglandin E(2) accelerate mucosal recovery from stress-induced gastric lesions via inhibition of apoptosis. 1159 61

Seven structurally related flavonoids including luteolin, nobiletin, wogonin, baicalein, apigenin, myricetin and fisetin were used to study their biological activities on the human leukemia cell line, HL-60. On MTT assay, wogonin, baicalein, apigenin, myricetin and fisetin showed obvious cytotoxic effects on HL-60 cells, with wogonin and fisetin being the most-potent apoptotic inducers among them. The cytotoxic effects of wogonin and fisetin were accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including DNA fragmentation, apoptotic bodies and the sub-G1 ratio. Treatment with an apoptosis-inducing concentration of wogonin or fisetin causes rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity. Further, cleavage of poly(ADP-ribose) polymerase (PARP) and decrease of pro-caspase 3 protein were detected in wogonin- and fisetin-treated HL-60 cells. An increase in the pro-apoptotic protein, bax, and a decrease in the anti-apoptotic protein, Mcl-1, were detected in fisetin- and wogonin-treated HL-60 cells. However, Bcl-2, Bcl-XL, and Bad all remained unchanged in wogonin- and fisetin-treated HL-60 cells. In vitro chromatin digestion revealed that endonuclease activity was profoundly enhanced in wogonin- and fisetin-treated HL-60 cells, and the addition of ethylenediaminetetraacetic acid (EDTA) or ethyleneglycoltetraacetic acid (EGTA) into the reaction blocked endonuclease activation and at an optimum pH of 7.5. The caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor, Ac-YVAD-CHO, attenuated wogonin- and fisetin-induced DNA ladders, PARP cleavage, and endonuclease activation. Pretreatment of HL-60 cells with N-acetyl-cysteine or catalase efficiently inhibited H(2)O(2) (200 microM)-induced apoptosis, but showed no inhibitory effect on wogonin- and fisetin-induced DNA ladders, caspase 3 activation, or bax protein induction. Decrease in endogenous ROS production was detected in wogonin- and fisetin-treated HL-60 cells by DCHF-DA assay. In conclusion, our experiments indicate that a decrease in intracellular peroxide level was involved in wogonin- and fisetin-induced apoptosis; activation of caspase 3 and endonuclease, induction of bax protein and suppression of Mcl-1 protein were detected in the process.
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PMID:Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease. 1184 97

Ceramide induces apoptotic cell death in a dose- and time-dependent manner in neuroblastoma SKN-SH cells. Pretreatment with caspase inhibitors blocks cell death, suggesting that a set of caspase activities including caspase 1, as well as caspase 3, are involved in ceramide-induced apoptosis in SKN-SH cells. Treatment with a caspase inhibitor 3 h after ceramide addition did not inhibit cell death, although caspase activity was substantially reduced. Ceramide-induced apoptosis is accompanied by accumulation of p53 followed by an increase of Bax and decrease of Bcl-2 levels. Inhibition of p53 expression with p53 antisense oligonucleotides inhibits apoptosis and prevents the increase in Bax and decrease in Bcl-2. Furthermore, pretreatment with p53 antisense oligonucleotides markedly inhibits the induction of caspase activity. These results suggest that p53 regulates the ratio Bcl-2/Bax and the expression/activation of caspases during ceramide-induced apoptosis in SKN-SH cells. Caspase inhibition did not alter the expression of p53, Bcl-2 and Bax. Thus ceramide-induced reduction in the Bcl-2/Bax ratio, increase in caspase activity, and apoptosis is dependent upon increases in cellular p53 levels which play a critical role in the regulation of apoptotic cell death.
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PMID:P53 mediates ceramide-induced apoptosis in SKN-SH cells. 1196 Mar 74

We studied the molecular events underlying butyrate-induced apoptosis in two different colon cancer cell lines: Caco-2, a well defined cancer cell and RSB, a cell line obtained from a colonic tumor of an ulcerative colitis patient. Caco-2 and RSB cells were exposed to 2, 5 and 10 mmol/L butyrate for 48 h. Caspase-1 was cleaved in Caco-2-cells at all butyrate concentrations, whereas in RSB-cells caspase-1 expression was undetectable. In RSB cells, butyrate dose-dependently induced caspase-3 cleavage, whereas in Caco-2-cells, butyrate up-regulated expression of the caspase-3 active subunit. Caspase-3-specific activity, cytoplasmic nucleosome concentration and growth were directly correlated with butyrate doses in both cell lines; however, the response was more pronounced in Caco-2 than in RSB cells. Expression of the cleaved poly(ADP-ribose) polymerase (PARP) product was elevated in both cell lines at the highest butyrate concentration. Bak expression gradually increased as a function of butyrate concentrations in both cell lines. At 10 mmol/L butyrate, expression increased by fivefold and sevenfold in Caco-2 and RSB cells, respectively. The highest expression of Bcl-2 was observed in control Caco-2 cells, and expression decreased with increasing butyrate concentration. This effect was not observed in RSB cells. Inactivation of caspase-1 with Z-YVAD-FMK abrogated butyrate-induced apoptosis in Caco-2 but not in RSB cells. Inactivation of caspase-3 with Z-DVED-FMK completely inhibited butyrate-induced apoptosis in RSB cells whereas this effect was less pronounced in Caco-2 cells. Our data demonstrate that butyrate-induced apoptosis is activated via different apoptotic pathways in diversely stratified colon cancers.
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PMID:Different molecular events account for butyrate-induced apoptosis in two human colon cancer cell lines. 1209 52


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