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 order to observe the expression of Fas, FasL and Bcl-2 and apoptosis of bone marrow CD34(+) cells in patients with myelodysplastic syndrome (MDS), and to explore the relation between the expression of these antigens and apoptosis, the expression of Fas, FasL and Bcl-2 and apoptosis of bone marrow CD34(+) cell were evaluated by flow cytometry in 26 patients with MDS including 9 cases of refactory anemia (RA), 1 case of RA with ringed sideroblasts (RAS), 9 cases of RA with excess blasts (RAEB) and 7 cases of RAEB in transformation (RAEB-t), 10 patients with acute myeloid leukemia (AML) and 6 control patients with normal bone marrow. The results showed that the expression of Fas and FasL of CD34(+) cells significantly increased in all types of MDS patients compared with control group (P < 0.01). The expression of Bcl-2 on CD34(+) cells in RAEB and RAEB-t patients was much higher as compared with that in control group (P < 0.01), but there was no significant difference between RA/RAS patients and control group (P > 0.05). The expression rates of Fas on CD34(+) cells were almost identical in all kinds of MDS, but there was significant difference on the expression of Bcl-2 (RA/RAS < RAEB < RAEB-t). Apoptosis of CD34(+) cells significantly increased in RA/RAS and RAEB patients compared with control group (P < 0.01), but there was no difference between RAEB-t and control group. Moreover, apoptosis of CD34(+) cells in control much higher than that in AML group (P < 0.01). There was no correlation between the expression of Fas or FasL and apoptosis on CD34(+) cell of MDS patients. Nevertheless, there was a negative correlation between the expression of Bcl-2 and apoptosis. It is concluded that apoptosis of CD34(+) cells was affected by a lot of factors in MDS, in which Bcl-2 is an important factor of depressing apoptosis. During the progress from MDS to AML, apoptosis changes from overgoing to deficiency in CD34(+) cell.
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PMID:[Expression of Fas, FasL and Bcl-2 and apoptosis of bone marrow CD34+ cells in patients with myelodysplastic syndrome]. 1284 12

BAG-1 has been identified as a Bcl-2-binding protein that inhibits apoptosis, either alone or in co-operation with Bcl-2. Here we show that BAG-1 inhibits p53- induced apoptosis in the human tumour cell line Saos-2. In contrast, BAG-1 was unable to inhibit the p53-independent pathway induced by apoptin, an apoptosis-inducing protein derived from chicken anaemia virus. Whereas BAG-1 seemed to co-operate with Bcl-2 to repress p53-induced apoptosis, co-expression of these proteins had no inhibitory effect on apoptin-induced apoptosis. Moreover, Bcl-2, and to some extent also BAG-1, paradoxically enhanced the apoptotic activity of apoptin. These results demonstrate that p53 and apoptin induce apoptosis through independent pathways, which are differentially regulated by BAG-1 and Bcl-2.
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PMID:BAG-1 inhibits p53-induced but not apoptin-induced apoptosis. 1464 36

Biliary tract cancer, or cholangiocarcinoma, has a poor prognosis. Resection is the only curative treatment, but only a minority of patients are eligible. Chemotherapy and gamma-irradiation are merely palliative, as they are unable to remove the malignancy completely. The chicken anemia virus-derived protein apoptin induces apoptosis in a wide range of human tumor cells and is not hindered by mutations inactivating p53 or by overexpression of Bcl-2, changes known to frustrate chemotherapy and radiation therapy. We examined whether apoptin kills human biliary tract cancer cells. Expression of apoptin by means of plasmids caused extensive cell death in three independent cholangiocarcinoma cell lines, CC-LP, CC-SW, and Mz-ChA-1, regardless of their oncogenic mutations, which included inactivated p16 and p53 and the disruption of the transforming growth factor beta signaling pathway. In vitro delivery of apoptin by an adenoviral vector completely eradicated cholangiocarcinoma cells. Moreover, coexpression of the broad-spectrum caspase inhibitor p35 with apoptin only delayed the induced cell death. Changes in nuclear morphology still occurred early after transfection, and nuclei eventually disintegrated, suggesting that apoptin-induced cell death in these cells is not blocked by mutations in either the initiation or execution phase of apoptosis. The efficient induction of cell death by apoptin in cholangiocarcinoma cell lines makes apoptin an attractive candidate for molecular therapy of biliary tract cancer.
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PMID:The tumor-selective viral protein apoptin effectively kills human biliary tract cancer cells. 1464 20

Mechanisms underlying the multiple developmental defects observed in Fanconi anemia (FA) patients are not well defined. We have identified the zebrafish homolog of human FANCD2, which encodes a nuclear effector protein that is monoubiquitinated in response to DNA damage, targeting it to nuclear foci where it preserves chromosomal integrity. Fancd2-deficient zebrafish embryos develop defects similar to those found in children with FA, including shortened body length, microcephaly, and microophthalmia, which are due to extensive cellular apoptosis. Developmental defects and increased apoptosis in Fancd2-deficient zebrafish were corrected by injection of human FANCD2 or zebrafish bcl2 mRNA, or by knockdown of p53, indicating that in the absence of Fancd2, developing tissues spontaneously undergo p53-dependent apoptosis. Thus, Fancd2 is essential during embryogenesis to prevent inappropriate apoptosis in neural cells and other tissues undergoing high levels of proliferative expansion, implicating this mechanism in the congenital abnormalities observed in human infants with FA.
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PMID:Knockdown of zebrafish Fancd2 causes developmental abnormalities via p53-dependent apoptosis. 1466 12

In 1990, the chicken anemia virus (CAV) genome was cloned by us and proven to be representative for CAV isolates worldwide. This genome contains unique promoter/enhancer replication elements and genes. Upon infection of its target cells, CAV replicates via a double-stranded (ds) DNA intermediate. From this ds CAV molecule, a single mRNA is transcribed, which encodes for three distinct proteins VP1, VP2, and VP3 or apoptin. Its capsid contains only the VP1 protein. However, for the production of the neutralizing epitope, co-synthesis of VP1 and VP2 are needed. CAV genomes with mutations in the 12 bp insert of the promoter/enhancer region were shown to produce immunogenic functional CAV particles. Mutations in these and other regulatory elements of CAV might also decrease its virus load resulting in a reduced pathogenic effect. CAV causes fatal cytopathogenic effects in e.g. chicken thymocytes via apoptosis. Under in vitro conditions, CAV replicates only in transformed chicken cell lines, which indicates that at least a part of the CAV life-cycle requires transformed-like cellular events. In these transformed cell lines, the synthesis of the apoptin protein alone mimics the CAV-induced apoptosis, whereas the VP2 protein also harbors some apoptotic activity. Extensive studies on apoptin resulted in the characterization of domains essential for its apoptotic activity and nuclear localization, which seems to be related with its ability to induce apoptosis. Therefore, both VP2 and apoptin are of interest in reducing the pathogenicity of CAV infections. A series of biomedical studies on apoptin have been carried out in human cell systems, which are informative about the mechanism of CAV-induced apoptosis in chicken (transformed) cells. Synthesis of apoptin alone induces apoptosis in various human transformed and/or tumorigenic cell lines, but not in normal human diploid cells. A striking difference in the cellular localization of apoptin was observed in human normal diploid cells versus tumor cells. In all tumor cells, apoptin is located mainly in the heterochromatic regions of the nucleus, whereas in normal cells it is present in peri-nuclear structures. Apoptin contains a bipartite nuclear localization signal, and one domain that resemble a nuclear export signal. Elucidation of parts of the apoptin-induced apoptotic pathway revealed unique characteristics: apoptin-induced apoptosis is independent of the tumor suppressor p53. The anti-apoptotic protein Bcl-2 does not inhibit but even accelerates apoptin-induced apoptosis in tumor cells, whereas over expression of Bcl-2 in normal cells has no effect on the apoptin activity. Upstream caspases are not involved, whereas downstream caspase 3 is, but seems not to be essential. A number of novel proteins were shown to interact with apoptin in transformed cells. Future studies of apoptin, VP2 and related cellular proteins in chicken cells will unravel the regulatory aspects of CAV-induced apoptosis.
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PMID:Chicken anemia virus induced apoptosis: underlying molecular mechanisms. 1474 Nov 20

Cancer is a growing problem for human health world-wide. Dramatic breakthroughs have increased our understanding of the molecular mechanisms involved in the process of tumorigenesis, allowing us to develop more refined anti-cancer treatments, expanding the repertoire of available anti-cancer drugs, and increasing the efficiency of their delivery to malignant cells. Nevertheless, even with improved understanding of the complex origins of cancer cells, there is a dearth of efficient and above all specific anti-cancer treatments. Apoptin (viral protein 3 - VP3), a gene product derived from the Chicken Anaemia Virus (CAV) represents a novel anti-cancer tool. It appears to have innate tumour-specific p53-independent, Bcl-2-enhanced pro-apoptotic activity, and hence may be of great utility in the endeavour to achieve specific and efficient elimination of cancer cells, particularly in cases of drug resistance through Bcl-2 overexpression/loss of p53 function etc. This review will examine the unique aspects of apoptin's properties, and in particular, its ability to localise specifically in the nucleus of transformed but not normal cells. The latter ability, importantly, appears to be integrally related to its tumour-specific pro-apoptotic action.
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PMID:The tumour specific pro-apoptotic factor apoptin (Vp3) from chicken anaemia virus. 1501 51

Nutrient deprivation during ischemia leads to severe insult to neurons causing widespread excitotoxic damage in specific brain regions such as the hippocampus. One possible strategy for preventing neurodegeneration is to express therapeutic proteins in the brain to protect against excitotoxicity. We investigated the utility of equine infectious anemia virus (EIAV)-based vectors as genetic tools for delivery of therapeutic proteins in an in vivo excitotoxicity model. The efficacy of these vectors at preventing cellular loss in target brain areas following excitotoxic insult was also assessed. EIAV vectors generated to overexpress the human antiapoptotic Bcl-2 or growth factor glial-derived neurotrophic factor (GDNF) genes protected against glutamate-induced toxicity in cultured hippocampal neurons. In an in vivo excitotoxicity model, adult Wistar rats received a unilateral dose of the glutamate receptor agonist N-methyl-D-aspartate to the hippocampus that induced a large lesion in the CA1 region. Neuronal loss could not be protected by prior transduction of a control vector expressing beta-galactosidase. In contrast, EIAV-mediated expression of Bcl-2 and GDNF significantly reduced lesion size thus protecting the hippocampus from excitotoxic damage. These results demonstrate that EIAV vectors can be effectively used to deliver putative neuroprotective genes to target brain areas and prevent cellular loss in the event of a neurological insult. Therefore these lentiviral vectors provide potential therapeutic tools for use in cases of acute neurotrauma such as cerebral ischemia.
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PMID:Lentiviral-mediated delivery of Bcl-2 or GDNF protects against excitotoxicity in the rat hippocampus. 1558 9

Apoptin, a small protein derived from chicken anemia virus, can specifically induce apoptosis in transformed cells or tumor cells, but not in normal cells. The tumor specificity of Apoptin relates to its subcellular localization. In transformed cells or tumor cells, Apoptin migrates to the nuclei, whereas in non-transformed cells, it remains mainly within the cytoplasm. Phosphorylation is responsible for the nuclear localization of Apoptin. In tumor cells, Apoptin is phosphorylated, then translocates into the nuclei, and induces cell apoptosis. Apoptin-induced apoptosis does not depend on functional p53, and can't be inhibited by overexpression of Bcl-2 and Bcl-xL, but caspase-3 activation is necessary for Apoptin-induced rapid apoptosis. Apoptin has a strong tendency to aggregate, and exists as aggregates in living cells, but in vivo formation and dissociation of the aggregates are not required for apoptosis-inducing activity of Apoptin. It is possible that Apoptin's ability to bind DNA closely relates to its ability to induce apoptosis.
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PMID:[Molecular mechanism of specific induction of apoptosis in tumor cells by apoptin]. 1582 81

Apoptin, a small proline-rich protein derived from the chicken anaemia virus, induces cell death selectively in cancer cells. The signalling pathways of apoptin-induced, cancer cell-selective apoptosis are not well understood. Here, we demonstrate that apoptin triggers apoptosis by activating the mitochondrial/intrinsic pathway, and that it acts independently of the death receptor/extrinsic pathway. Jurkat cells deficient in either FADD or caspase-8 (which are both necessary for the extrinsic pathway) were equally as sensitive to apoptin as their parental clones. This demonstrates that apoptin is likely to act through the mitochondrial death pathway. Apoptin treatment causes a loss of mitochondrial membrane potential, and release of the mitochondrial proteins cytochrome c and apoptosis-inducing factor. Apoptin-induced cell death is counteracted by the anti-apoptotic Bcl-2 family members, Bcl-2 itself and Bcl-XL, as shown in Jurkat leukaemia cells. In addition, we describe the processing and activation of caspase-3. By contrast, cleavage of caspase-8, which is predominantly triggered by the death receptor pathway, is not observed. Furthermore, apoptin triggers the cytoplasmic translocation of Nur77, and the inhibition of Nur77 expression by siRNA significantly protects MCF7 cells from apoptin-triggered cell death. Thus, our data indicate that the apoptin death signal(s) ultimately converges at the mitochondria, and that it acts independently of the death receptor pathway.
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PMID:Cancer-specific toxicity of apoptin is independent of death receptors but involves the loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators by a Nur77-dependent pathway. 1617 7

Fanconi anaemia (FA) is a rare genetic disease whose patients have a high predisposition to haematological abnormalities and cancer. Fas expression levels in peripheral blood lymphocytes samples of 73 FA patients were measured to verify if alterations in Fas expression could lead to predisposition/resistance to spontaneous or PHA induced apoptosis, as well as, to reflect some haematological features of this disease. The anti- and pro-apoptotic proteins Bcl-2 and Bax were also evaluated. FA patients samples could be divided into three different groups based on Fas expression: 20 samples had low, 32 normal and 21 increased Fas levels when compared to 41 control samples. No correlation was found between Fas and Bcl-2 expression but a good association was obtained with Bax, in the subgroup with increased Fas expression. The best correlation was seen between Bax expression and apoptosis. Out of the 15 samples with high Bax expression, 11 underwent apoptosis whereas only one out of seven samples with low levels of Bax displayed increased induced apoptosis. Most patients with normal haematological features expressed Fas within normal levels. It is difficult to establish, however, if Fas-expression is involved in the cause or is a consequence of the effects observed.
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PMID:Apoptosis and expression of anti- and pro-apoptotic proteins in peripheral blood mononuclear cells of Fanconi anaemia patients: a study of 73 cases. 1619 Oct 87


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