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 induction of apoptosis in T cells is one of several mechanisms by which tumors escape immune recognition. We have investigated whether tumors induce apoptosis in dendritic cells (DC) by co-culture of murine or human DC with different tumor cell lines for 4-48 h. Analysis of DC morphological features, JAM assay, TUNEL, caspase-3-like and transglutaminase activity, Annexin V binding, and DNA fragmentation assays revealed a time- and dose-dependent induction of apoptosis in DC by tumor-derived factors. This finding is both effector and target specific. The mechanism of tumor-induced DC apoptosis involved regulation of Bcl-2 and Bax expression. Double staining of both murine and human tumor tissues confirmed that tumor-associated DC undergo apoptotic death in vivo. DC isolated from tumor tissue showed significantly higher levels of apoptosis as determined by TUNEL assay when compared with DC isolated from spleen. These findings demonstrate that tumors induce apoptosis in DC and suggest a new mechanism of tumor escape from immune recognition. DC protection from apoptosis will lead to improvement of DC-based immunotherapies for cancer and other immune diseases.
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PMID:Tumor's other immune targets: dendritic cells. 1044 78

Enhanced apoptosis characterizes several pathologies affecting human liver. This study sought to determine whether apoptosis is involved in the formation of fibrotic lesions occurring in hepatic disease. The expression of Bcl-2 was analysed, and of 'tissue' transglutaminase (tTG), a cross-linking enzyme which recent evidence suggests plays a role in the formation of fibrotic lesions in experimental settings. Regardless of the degree of liver injury, tTG abnormally accumulated in the liver cells adjacent to fibrotic tissue. Many cells showing DNA fragmentation and morphological features of apoptosis were also observed near fibrotic lesions. Bcl-2 was detected predominantly in infiltrating lymphocytes within the liver tissue. Marked staining for both tTG protein and chromatin was also observed in the acellular fibrotic tissue, which suggested an active release of intracellular macromolecules from the dying cells into the extracellular matrix. This study indicates that fibrogenesis in the liver is associated with the release of tTG from dying cells. By cross-linking extracellular matrix proteins, this enzyme might play a role in the formation of fibrotic lesions.
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PMID:'Tissue' transglutaminase release from apoptotic cells into extracellular matrix during human liver fibrogenesis. 1045 94

Treatment of the human promonocytic cell line U937 with all-trans-retinoic acid (RA) commits these cells to apoptosis, which can be triggered by simply increasing intracellular calcium levels by the ionophore A23187. RA treatment of U937 cells is characterized by a decrease in Bcl-2 and marked induction of "tissue" transglutaminase (tTG) gene expression. In this study, we show that the inhibition of tTG expression in U937 cells undergoing apoptosis prevents their death. In fact, U937 cell-derived clones transfected with the human tTG gene in the antisense orientation showed a pronounced decrease in apoptosis induced by several stimuli. These findings demonstrate that the Ca(2+)-dependent irreversible cross-linking of intracellular proteins catalyzed by tTG represents an important biochemical event in the gene-regulated cell death in monoblasts. In addition, our data indicate that the apoptotic program in promonocytic cells is strictly regulated by RA and that a key role is played by the free intracellular calcium concentration.
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PMID:Inhibition of "tissue" transglutaminase increases cell survival by preventing apoptosis. 1056 82

In thymocytes, peroxynitrite induces poly(ADP-ribose) synthetase (PARS) activation, which results in necrotic cell death. In the absence of PARS, however, peroxynitrite-treated thymocytes die by apoptosis. Because Bcl-2 has been reported to inhibit not only apoptotic but also some forms of necrotic cell death, here we have investigated how Bcl-2 regulates the peroxynitrite-induced apoptotic and necrotic cell death. We have found that Bcl-2 did not provide protection against peroxynitrite-induced necrotic death, as characterized by propidium iodide uptake, mitochondrial membrane potential decrease, secondary superoxide production, and cardiolipin loss. In the presence of a PARS inhibitor, peroxynitrite-treated thymocytes from Bcl-2 transgenic mice showed no caspase activation or DNA fragmentation and displayed smaller mitochondrial membrane potential decrease. These data show that Bcl-2 protects thymocytes from peroxynitrite-induced apoptosis at a step proximal to mitochondrial alterations but fails to prevent PARS-mediated necrotic cell death. Activation of tissue transglutaminase (tTG) occurs in various forms of apoptosis. Peroxynitrite did not induce transglutaminase activity in thymocytes and did not have a direct inhibitory effect on the purified tTG. Basal tTG was not different in Bcl-2 transgenic and wild type cells.
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PMID:BCL-2 protects peroxynitrite-treated thymocytes from poly(ADP-ribose) synthase (PARS)-independent apoptotic but not from PARS-mediated necrotic cell death. 1105 71

Several protocols for the adjuvant treatment of glioblastoma multiforme (GBM) are currently being evaluated. In this context, little is known about the influence of radiochemotherapy on apoptosis and the expression of apoptosis-related proteins in vivo. We have analyzed the incidence of apoptosis using in situ nick translation (ISNT) and expression of Ki-67 (MIB- 1), p53 (DO-1 and DO-7), Bcl-2 and transglutaminase II (TGase II) by immunohistochemistry in 41 patients with GBM and their matched relapses. Sixteen patients received radiochemotherapy, 18 irradiation and 7 no treatment. Radiochemotherapy resulted in an increase in Bcl-2+ cells (p = 0.013). Irradiation caused the reduction of MIB-1+ (p = 0.0015), DO-7+ (p = 0.0043) and the increase of Bcl-2+ cells (p = 0.016). We calculated a positive correlation between high TGase II scores in patients preceding radiochemotherapy (p = 0.0186) and no treatment (p = 0.0158), low ISNT scores (p = 0.0018) and high DO-1 scores (p = 0.0233) in patients preceding irradiation and short time to progression. These data show that distinct postsurgical radiochemotherapy protocols differentially alter cellular proliferation and expression of p53 and Bcl-2 in GBM relapses. Furthermore, we show that ISNT, DO-I and TGase II labeling scores are therapy-specific predictors of time to progression in GBM patients.
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PMID:Distinct radiochemotherapy protocols differentially influence cellular proliferation and expression of p53 and Bcl-2 in glioblastoma multiforme relapses in vivo. 1108 75

The susceptibility to undergo apoptosis of fresh human peripheral blood mononuclear cells (PBMCs) from three groups of healthy donors of different ages: young people (19-40 years), old people (65-85 years) and centenarians was assessed. Apoptosis was induced by 2-deoxy-D-ribose (dRib), an agent which induces apoptosis in quiescent PBMCs by interfering with cell redox status and mitochondrial membrane potential (MMP). Our major finding is that an inverse correlation emerged between the age of the donors and the propensity of their PBMCs to undergo dRib-induced apoptosis. PBMCs from old people and centenarians also showed an increased resistance to dRib-induced glutathione depletion and a decreased tendency to lose MMP. The anti-apoptotic molecule Bcl-2 was similarly expressed in PBMCs from the three age groups. Moreover, the plasma level of the stable product of transglutaminase, epsilon(gamma-glutamyl)lysine isodipeptide, a marker of total body apoptotic rate, was decreased in centenarians compared to young and elderly people. On the whole, these findings suggest that physiological aging is characterised by a decreased tendency to undergo apoptosis, a phenomenon likely resulting from adaptation to lifelong exposure to damaging agents, such as reactive oxygen species, and may contribute to one of the major phenomena of immunosenescence, i.e. the progressive accumulation of memory/effector T cells.
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PMID:Decreased susceptibility to oxidative stress-induced apoptosis of peripheral blood mononuclear cells from healthy elderly and centenarians. 1116 77

The apoptosis-inducing capacity of aqueous garlic extract during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch (HBP) carcinogenesis was investigated in male Syrian hamsters using DNA fragmentation and the apoptosis-associated proteins, tissue transglutaminase (tTG) and Bcl-2. Hamsters were divided into four groups of six animals each. Animals in group 1 were painted with a 0.5% solution of DMBA in liquid paraffin on the right buccal pouches three times a week for 14 weeks. Group 2 animals painted with DMBA as in group 1, in addition received 250 mg/kg body weight aqueous garlic extract orally on days alternate to DMBA application. Group 3 animals received garlic extract as in group 2. Group 4 animals received neither DMBA nor garlic extract and served as the control. The experiment was terminated at the end of 14 weeks. Administration of aqueous garlic extract (250 mg/kg body weight) to animals painted with DMBA inhibited DMBA-induced oral carcinogenesis as revealed by the absence of neoplasms, induction of tTG and inhibition of Bcl-2 expression. The results of the present study suggest that garlic may exert its chemopreventive effect by inducing apoptosis.
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PMID:Garlic induces apoptosis during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. 1211 Mar 36

The apoptosis-inducing capacity of S-allylcysteine (SAC), a water-soluble garlic constituent, during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch (HBP) carcinogenesis was investigated in male Syrian hamsters using DNA fragmentation and the apoptosis-associated proteins, tissue transglutaminase (tTG) and Bcl-2. Hamsters were divided into four groups of six animals each. Animals in group 1 were painted with a 0.5% solution of DMBA in liquid paraffin on the right buccal pouches three times a week for 14 weeks. Group 2 animals painted with DMBA as in group 1, in addition received 200 mg kg(-1) body weight SAC orally on days alternate to DMBA application. Group 3 animals received SAC as in group 2. Group 4 animals received neither DMBA nor SAC and served as the control. The experiment was terminated at the end of 14 weeks. Administration of SAC (200 mg kg(-1) body weight) to animals painted with DMBA inhibited DMBA-induced HBP carcinogenesis as revealed by the absence of neoplasms, induction of tTG and inhibition of Bcl-2 expression. The results of the present study suggest that SAC may exert its chemopreventive effect by inducing apoptosis.
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PMID:Apoptosis induction by S-allylcysteine, a garlic constituent, during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. 1212 4

Mechanisms leading to morphological changes of the small intestine during coeliac disease (CD) are not yet completely recognized; however, two main processes have been suggested recently: remodeling of mucosa by matrix metalloproteinases, and mucosal atrophy by apoptosis. The aim of this study was analysis of the expression of proteins regulating apoptosis in the small intestine of children with active CD (ACD) and potential CD (PCD). Jejunal biopsies of 43 children with PCD and untreated ACD and 21 control samples were analyzed by means of standard indirect immunohistochemical technique for Fas, Fas ligand (Fas-L), tissue transglutaminase (tTG), Bcl-2, and glutathione S-transferase (GST) expression. We found significantly lower numbers of Fas-expressing enterocytes in the ACD patients than in PCD patients and controls. Similarly, the number of Fas-positive mucosal lymphocytes was decreased in ACD when compared with PCD. The number of Fas-L- and tTG-expressing enterocytes and mucosal lymphocytes was higher in both PCD and ACD. On the other hand, the number of Bcl-2-positive mucosal lymphocytes in PCD as well as ACD was significantly lower. The expression of tTG in extracellular matrix was significantly higher in PCD and ACD when compared with controls. Our results showed that Fas and/or Fas-L, Bcl-2, and tTG may be involved in apoptotic pathways leading to mucosal atrophy in children with CD. tTG changes are in agreement with the presumed role of this protein in the pathogenesis of CD.
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PMID:Immunohistochemical study of the apoptotic mechanisms in the intestinal mucosa during children's coeliac disease. 1269 66

Anaplastic meningiomas (MIIIs) and meningeal hemangiopericytomas (HPCs) display significant morphologic and immunohistochemical overlap, including occasional cases of otherwise classic HPC with focal epithelial membrane antigen (EMA) positivity. The availability of several new biomarkers prompted us to examine the potential diagnostic roles of ancillary immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) studies. From the archival university neuropathology and consult files of 1 of the authors (A.P.), 19 meningeal HPCs and 19 MIIIs were retrieved for further study. IHC was performed by using EMA, CAM 5.2, CD99, Bcl-2, claudin-1 and Factor XIIIa (FXIIIa) antibodies. FISH was performed with NF2, 4.1B (DAL-1), chromosome 1p32, and 14q32 probes. HPCs showed strong CD99 (85% of cases), strong bcl-2 (86%), focal EMA (33%), focal claudin-1 (13%), and scattered individual cell FXIIIa (100%) positivity. MIIIs showed strong EMA (89%), strong claudin-1 (54%), weak or focal CD99 (15%), weak or focal bcl-2 (31%), and individual cell FXIIIa (84%) positivity. Focal CAM 5.2 expression was seen in 26% of HPCs and 15% of MIIIs. Deletions were extremely common in MIIIs: 1p (94%), 14q (67%), NF2 (100%), and 4.1B (67%). HPCs showed no 14q or 4.1B deletions, with 1 case each of 1p and NF2 deletions (6%). The sensitivities and specificities of the 3 most useful IHC markers (EMA, CD99, bcl-2) were 85%-89% and 67%-84%, respectively. The sensitivity and specificity of claudin-1 for MIII were 54% and 86%, respectively. The specificity and positive predictive value of combined CD99 and bcl-2 expression for the diagnosis of HPC was 95%. The sensitivities of individual genetic markers were 67%-100%, with specificities of 94%-100%. Our 3 conclusions were as follows: (1) EMA, CD99, bcl-2, and claudin-1 IHC and 1p, 14q, NF2, and 4.1B FISH are particularly useful for distinguishing anaplastic meningiomas from meningeal HPCs. (2) Focal EMA expression does not preclude a diagnosis of HPC. (3) The characteristic FXIIIa staining pattern reported for HPC also is encountered frequently in anaplastic meningiomas and therefore is nonspecific in this diagnostic setting.
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PMID:Anaplastic meningioma versus meningeal hemangiopericytoma: immunohistochemical and genetic markers. 1566


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