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)

Two p53-null T lymphoma cell lines proved to be highly sensitive to inhibition of gene expression. With either actinomycin D or cycloheximide, apoptosis commenced within 2 h, as indicated by loss of membrane integrity, degradation of certain proteins (including the phosphatase calcineurin) and DNA fragmentation. These effects were ablated by co-expression of Bcl-2 or co-incubation with the caspase inhibitor Z-VAD-fmk. These results suggest that the apoptotic machinery is in place in these cells but held in check by an unknown labile protein, which probably acts upstream of Bcl-2. Although cycloheximide can activate the JNK or p38 MAP kinases in some cells, neither was implicated here. However, disruption of phosphoinositide 3-kinase signaling may be involved, because the cells were also sensitive to wortmannin. The high sensitivity of the p53-null lymphoma cells to inhibitors of gene expression suggests that such inhibitors might prove useful in the cytotoxic therapy of certain tumors.
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PMID:Interference with gene expression induces rapid apoptosis in p53-null T lymphoma cells. 1063 38

Oral carcinomas frequently contain human papilloma virus (HPV)-16/18. As p53 is degraded through interaction with HPV-16/18 products (E6/E7), p53 dysfunction may contribute to oral carcinogenesis. Furthermore, epidemiological studies suggest that smoking history may be critical for oral carcinogenesis. To delineate the involvement of HPV-16 infection and carcinogen in oral carcinogenesis, Park et al have established a multistep oral carcinogenesis model. Overexpression of p53 altered the expression of Fas antigen (Fas-R), Bax and Bcl-2; however, it remains unclear how the loss of p53 modifies the expression of these molecules. Using the multistep oral carcinogenesis model, we analyzed how the loss of p53 and carcinogen modified the expression of these molecules and their role in the development of resistance to apoptosis of oral carcinomas. The HOK-16B cell line was immortalized by HPV-16 transfection of normal human oral keratinocytes (NHOK). HOK-16B-BaP and HOK-16B-BaP-T1 were established from HOK-16B following short-term and long-term stimulation with the chemical carcinogen, benzo(a)pyrene, respectively. The malignant phenotype develops in sequence from HOK-16B, HOK-16B-BaP and HOK-16B-BaP-T1. The expression of apoptosis-related molecules was examined by Western blot analysis or by flow cytometry. Fas-mediated cytotoxicity was assessed using CH-11, an agonistic anti-Fas-R IgM monoclonal antibody. The apoptosis-related molecules examined were the Fas-R, Bcl-2, Bax, and Fas-associated phosphatase 1 (FAP-1). Downregulation of Fas-R and upregulation of Bcl-2 in HOK-16B-BaP were observed in HOK-16B-BaP and HOK-16B-BaPT1. Bax was downregulated in HOK-16B, HOK-16B-BaP and HOK-16B-BaP-T1. The expression of FAP-1 was increased with progression towards malignancy. NHOK and HOK-16B were relatively sensitive to CH-11, whereas HOK-BaP and HOK-BaP-T1 were resistant to CH-11. Treatment of HOK-16B-BaP with antisense bcl-2 oligonucleotide rendered the cells more sensitive to CH-11-induced apoptosis. These data demonstrate that both the loss of p53 and carcinogen stimulation are associated with altered expression of Fas-R, Bcl-2 and FAP-1, although the loss of p53 is sufficient for altered expression of Bax. Thus, both HPV infection and smoking contribute to acquisition of anti-apoptotic characteristics by oral carcinomas.
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PMID:Both HPV and carcinogen contribute to the development of resistance to apoptosis during oral carcinogenesis. 1067 94

Suppression of apoptosis by survival factors is important for the maintenance of normal tissue homoeostasis and the response to infection or injury. Survival factors such as insulin-like growth factor-I (IGF-I) initiate a signalling cascade that starts by tyrosine phosphorylation of substrates leading to the activation of serine kinases that modulate the activity of members of the Bcl-2 family, which regulates the apoptotic machinery in most cells. Tumour cells often have enhanced survival mechanisms due either to up-regulation of the IGF-I receptor and its ligands or to loss of function of a phosphatase (PTEN) that regulates part of this survival pathway. The C-terminus of the IGF-I receptor appears to be a regulatory domain for the anti-apoptotic activity of this receptor, and certain residues within the C-terminus are essential for this regulatory activity. Knowledge of the proteins and pathways, which interact with these C-terminal domains, should lead us to ways of modulating IGF-I-mediated survival in tumours.
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PMID:Regulation of survival signals from the insulin-like growth factor-I receptor. 1081 97

MAP kinase-dependent phosphorylation processes have been shown to interfere with the degradation of the antiapoptotic protein Bcl-2. The cytosolic MAP kinase phosphatase MAP kinase phosphatase-3 (MKP-3) induces apoptosis of endothelial cells in response to tumor necrosis factor alpha (TNFalpha) via dephosphorylation of the MAP kinase ERK1/2, leading to Bcl-2 proteolysis. Here we report that the endothelial cell survival factor nitric oxide (NO) down-regulated MKP-3 by destabilization of MKP-3 mRNA. This effect of NO was paralleled by a decrease in MKP-3 protein levels. Moreover, ERK1/2 was found to be protected against TNFalpha-induced dephosphorylation by coincubation of endothelial cells with the NO donor. Subsequently, both the decrease in Bcl-2 protein levels and the mitochondrial release of cytochrome c in response to TNFalpha were largely prevented by exogenous NO. In cells overexpressing MKP-3, no differences in phosphatase activity in the presence or absence of NO were found, excluding potential posttranslational modifications of MKP-3 protein by NO. These data demonstrate that upstream of the S-nitrosylation of caspase-3, NO exerts additional antiapoptotic effects in endothelial cells, which rely on the down-regulation of MKP-3 mRNA.
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PMID:Nitric oxide down-regulates MKP-3 mRNA levels: involvement in endothelial cell protection from apoptosis. 1084 76

Fas transduces apoptotic signals upon cross-linking with the Fas ligand (FasL), which is experimentally replaced by agonistic anti-Fas monoclonal antibodies (mAb). Of eight human malignant hematopoietic cell lines (HL-60, KG-1, THP-1, K562, U937, Jurkat, IM-9, RPMI-8226) examined by flow cytometric analysis, all, except K562, were found to be positive for surface Fas antigen. However, despite surface Fas expression, the agonistic anti-Fas mAb (7C11) induced apoptosis in only three of seven Fas-expressing cell lines (KG-1, Jurkat and IM-9). This Fas-resistance did not correlated with high levels of mRNA either for DcR3, a decoy receptor for FasL, or for FAP-1, a Fas-associated phosphatase that can block the apoptotic function of Fas. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis did not show consistent differences in the expression of Bcl-2 and Bax between Fas-sensitive and Fas-resistant cell lines examined. These findings indicated that the presence or absence of mRNA expression of DcR3, FAP-1, Bcl-2 and Bax did not always correlate with relative sensitivity to Fas-mediated apoptosis. Treatment of cells with cycloheximide converted the phenotype of resistant cell lines from Fas-resistant to Fas-sensitive, and enhanced the sensitivity of Fas-sensitive cell lines. These results suggest that the Fas-resistance is dependent on the presence of labile proteins that determine resistance to Fas-mediated apoptosis and the apoptotic machinery is already in place in Fas-resistant cell lines.
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PMID:Fas-mediated apoptosis and expression of related genes in human malignant hematopoietic cells. 1119 Feb 79

Coenzyme Q10 (CoQ10) is a component of the antioxidant machinery that protects cell membranes from oxidative damage and decreases apoptosis in leukemic cells cultured in serum-depleted media. Serum deprivation induced apoptosis in CEM-C7H2 (CEM) and to a lesser extent in CEM-9F3, a subline overexpressing Bcl-2. Addition of CoQ10 to serum-free media decreased apoptosis in both cell lines. Serum withdrawal induced an early increase of neutral-sphingomyelinase activity, release of ceramide, and activation of caspase-3 in both cell lines, but this effect was more pronounced in CEM cells. CoQ10 prevented activation of this cascade of events. Lipids extracted from serum-depleted cultures activated caspase-3 independently of the presence of mitochondria in cell-free in vitro assays. Activation of caspase-3 by lipid extracts or ceramide was prevented by okadaic acid, indicating the implication of a phosphatase in this process. Our results support the hypothesis that plasma membrane CoQ10 regulate the initiation phase of serum withdrawal-induced apoptosis by preventing oxidative damage and thus avoiding activation of downstream effectors as neutral-sphingomyelinase and subsequent ceramide release and caspase activation pathways.
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PMID:Coenzyme Q protects cells against serum withdrawal-induced apoptosis by inhibition of ceramide release and caspase-3 activation. 1122 31

Interactions between the purine analogue 2-fluoroadenine 9-beta-D-arabinofuranoside (F-ara-A) and the kinase inhibitor UCN-01 have been examined in human leukemia cells (U937 and HL-60) with respect to induction of mitochondrial damage, caspase activation, apoptosis, and loss of clonogenic survival. Simultaneous or subsequent exposure of F-ara-A-treated cells (2 microM) to UCN-01 (100 nM) resulted in a marked potentiation of apoptosis, manifested by loss of mitochondrial membrane potential (delta psi(m)), cleavage/activation of procaspase-9 and procaspase-3, DNA fragmentation, and degradation of poly-ADP(ribosyl) polymerase. Coadministration of UCN-01 with F-ara-A was also associated with diminished phosphorylation of the cdc25 phosphatase. In contrast, exposure of cells to the sequence UCN-01, followed by F-ara-A, resulted in only a modest increase in apoptotic cells. The ability of UCN-01 to potentiate F-ara-A-mediated lethality was not mimicked by the selective PKC inhibitor bisindolylmaleimide, nor did treatment of cells with UCN-01 enhance formation of F-ara-ATP or increase incorporation of [3H]F-ara-A into DNA. Enhanced apoptosis in cells exposed sequentially or simultaneously to F-ara-A and UCN-01 was accompanied by a substantial reduction in colony formation (e.g., to 0.01% of control values). Cotreatment with UCN-01 also increased F-ara-A-mediated apoptosis and loss of delta psi(m) in U937 cells ectopically expressing Bcl-2, although not to the same extent as that observed in empty-vector controls. Finally, simultaneous exposure (24 h) of malignant B lymphocytes from the pleural effusion of a patient with indolent non-Hodgkin's lymphoma to F-ara-A and UCN-01 ex vivo resulted in a striking increase in apoptosis, as determined by terminal deoxynucleotidyltransferase-mediated nick end labeling assay. These findings indicate that UCN-01 increases F-ara-A-induced mitochondrial damage and apoptosis in human leukemia cells in a sequence-dependent manner, and that these events occur in at least some primary human lymphoma cells.
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PMID:Interactions between 2-fluoroadenine 9-beta-D-arabinofuranoside and the kinase inhibitor UCN-01 in human leukemia and lymphoma cells. 1123 87

We find that the prostate cancer cell lines ALVA-31, PC-3, and DU 145 are highly sensitive to apoptosis induced by TRAIL (tumor-necrosis factor-related apoptosis-inducing ligand), while the cell lines TSU-Pr1 and JCA-1 are moderately sensitive, and the LNCaP cell line is resistant. LNCaP cells lack active lipid phosphatase PTEN, a negative regulator of the phosphatidylinositol (PI) 3-kinase/Akt pathway, and demonstrate a high constitutive Akt activity. Inhibition of PI 3-kinase using wortmannin and LY-294002 suppressed constitutive Akt activity and sensitized LNCaP cells to TRAIL. Treatment of LNCaP cells with TRAIL alone induced cleavage of the caspase 8 and XIAP proteins. However, processing of BID, mitochondrial release of cytochrome c, activation of caspases 7 and 9, and apoptosis did not occur unless TRAIL was combined with either wortmannin, LY-294002, or cycloheximide. Blocking cytochrome c release by Bcl-2 overexpression rendered LNCaP cells resistant to TRAIL plus wortmannin treatment but did not affect caspase 8 or BID processing. This indicates that in these cells mitochondria are required for the propagation rather than the initiation of the apoptotic cascade. Infection of LNCaP cells with an adenovirus expressing a constitutively active Akt reversed the ability of wortmannin to potentiate TRAIL-induced BID cleavage. Thus, the PI 3-kinase-dependent blockage of TRAIL-induced apoptosis in LNCaP cells appears to be mediated by Akt through the inhibition of BID cleavage.
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PMID:Elevated AKT activity protects the prostate cancer cell line LNCaP from TRAIL-induced apoptosis. 1127 84

To evaluate the bcl-2 protein expression in non small cell lung carcinomas (NSCLC) as an index of apoptosis of these tumors, in fine needle aspiration biopsies (FNABs) of the lung, we studied thirty-eight cases of NSCLC (25 bronchogenic adenocarcinomas and 13 squamous. carcinomas. Bcl-2 protein was used as the primary antibody (monoclonal, DAKO) by Alkaline-phosphatase method. Very light haematoxylin was performed as the counterstain. The results were compared and confirmed histologically. A cytoplasmatic expression of the bcl-2 protein was found in 72% (18 out of 15) of the bronchogenic adenocarcinomas while 61.54% (8 out of 13) of squamous carcinomas showed bcl-2 expression. For the quantitative analysis of our results, we used the t-test and the difference between those two histologic types was regarded as statistically significant with p < 0.001.
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PMID:Bcl-2 expression as an apoptotic index in non small cell lung carcinomas. 1128 30

Lithium is an effective drug for both treatment and prophylaxis of bipolar disorder. However, the mechanism of lithium action is still unknown. The inositol depletion hypothesis is supported by biochemical and behavioral data in rats, but primate inositol levels are higher than in rodents and may obviate the effects of depletion. Inhibition of 5HT autoreceptors by lithium is supported by biochemical and behavioral data in rats but would seem more related to lithium's antidepressant than to its antimanic or prophylactic effects. Lithium induces increases in levels of the anti-apoptotic factor Bcl-2. This effect could be most relevant for treatment of neurodegenerative disorders. Lithium inhibits glycogen synthase kinase-3, which is involved in a wide range of signal transduction pathways. However, this lithium effect occurs at high concentrations and may be more relevant for its toxic effect. Lithium in low concentrations induces accumulation of PAP, which affects several cellular processes including RNA processing. However, PAP phosphatase is present more in peripheral tissues than in brain. This lithium effect could explain some of its peripheral side effects. Chronic lithium administration upregulates glutamate reuptake and thus decreases glutamate availability in synapse. Glutamate is an excitatory neurotransmitter and its reduction could exert an antimanic effect. Biochemical and clinical experiments are necessary to determine the key mechanism of lithium efficacy in treatment and prophylaxis of affective disorders.
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PMID:The mechanism of lithium action: state of the art, ten years later. 1138 81


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