Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokine-driven activation of hepatic stellate cells (HSC) in tissue injury and inflammation is a key pathogenetic event in liver fibrogenesis leading to an expanded pool of matrix producing myofibroblasts (MFB) which represent the transformed counterpart of HSC. We hypothesize that expansion of the pool of MFB might also be accomplished by modulation of apoptosis, which plays an opposite and complementary role to mitosis in the cellular homeostasis. We characterized the susceptibility of HSC in primary culture and of MFB in secondary culture to apoptosis induced by the soluble Fas ligand (sFasL) and related the effects to the expression levels of Fas (APO-1/CD95) and some major proapoptotic and contra-apoptotic protooncogenes. MFB showed a dose-dependent apoptotic reaction upon exposure to sFasL as evidenced by a strong increase of nucleosomal DNA fragments, loss of cellular DNA, positive TUNEL reaction, and annexin staining. The effect was found only if protein synthesis (cycloheximide) or RNA synthesis (actinomycin D) were arrested. HSC maintained for various times in primary culture were completely resistant to sFasL in combination with cycloheximide, but in late primary cultures (day 7 onward) an increasing susceptibility to sFasL-mediated apoptosis was developed. By semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR) analysis and alkaline phosphatase-anti-alkaline phosphatase staining Fas receptor was identified both in HSC and MFB at comparable expression levels. The expression of the contra-apoptotic protooncogenes bcl-2 and bcl-xl was found to be much stronger in early HSC than in late HSC and MFB as shown by ribonuclease protection assay. The expression of bcl-2 was additionally confirmed by semiquantitative RT-PCR and immunoblotting. Proapoptotic bax was found in comparable quantities at the RNA level in HSC and MFB but at the protein level MFB showed increased bax expression. It is concluded that transformation of HSC to MFB is paralleled by an increasing sensitivity to sFasL-mediated apoptosis, which might be related to a strong decrease of bcl-2 and bcl-xl expression, leading to a preponderance of proapoptotic gene expression in MFB. Modulation of apoptotic susceptibility of transforming HSC could be an important complementary pathway in the pathogenesis of fibrosis.
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PMID:Transformation-dependent susceptibility of rat hepatic stellate cells to apoptosis induced by soluble Fas ligand. 969 16

To elucidate the clinicopathological features of cutaneous allergic (leukocytoclastic) vasculitis (CAV), biopsied skin tissues of 32 patients with CAV were examined immunohistopathologically and compared with the main clinical features. Additionally, to obtain some clues to better understand the roles of infiltrating cells, particularly neutrophils in CAV, apoptosis and related antigens were investigated in vivo. The 32 patients with CAV were divided into two groups based on their clinical course: (i) non-recurrent (group I; nine cases); and (ii) recurrent (group II; 23 cases). Immunohistopathologically, group I was characterized by stereotypical necrotizing changes of CAV with fibrin exudation of small blood vessels in the upper cutis, and group II was characterized by CAV and fibrous thickening of the vascular walls with significant infiltration of CD3+, UCHL-1+ T cells. Group II was subdivided further: groups IIa (15 cases) and IIb (eight cases); that is, the former was notable for necrotizing changes of CAV, which tended to spread into the proper corium down to the lower cutis; whereas the latter exhibited considerably less marked histological changes of CAV without any spread to the lower cutis. In a comparison of the clinical data among the three groups, there were considerable differences in age, clinical course, localization of purpura and associated disease. In particular, group II showed a high frequency of connective tissue diseases. The presence of apoptosis was seen in a considerable number of neutrophils, and some nuclear debris turned out to be apoptotic bodies by the in situ terminal deoxytransferase (TdT)-catalyzed DNA nick end-labeling (TUNEL) method and electron microscopy. By combining immunohistochemistry with TUNEL, the majority of apoptotic neutrophils and nuclear debris was seen to be ingested by macrophages. In immunohistochemical examinations for apoptosis-related bcl-2 protein and Fas antigen, bcl-2 was recognized only in the cytoplasm of infiltrating T cells, and Fas was positively stained on the cellular membranes of infiltrating T cells and neutrophils in a scattered fashion. Thus, a novel method for neutrophil disposal in CAV was suggested.
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PMID:Cutaneous allergic vasculitis: clinicopathological characterization and identification of apoptosis. 977 9

Androgen ablation has been an effective treatment in patients with advanced prostate cancer. However, most treated patients develop hormonally resistant disease and do not respond to conventional chemotherapy. Immunotherapy against prostate cancer is an alternative approach in overcoming hormonal/drug-resistant prostate cancer. Cytotoxic immune lymphocytes kill target cells via the perforin/granzyme and the Fas-ligand (Fas-L) pathways. We hypothesize that tumor cells respond poorly to immunotherapy by developing resistance to killing by the Fas-L mechanism. This study investigated whether prostate tumor cells are sensitive to Fas-mediated killing. The human prostate carcinoma cell lines DU145, PC-3, and LnCAP were examined for their sensitivity to killing and apoptosis by the Fas-L agonist anti-Fas antibody and CTLs. All three lines moderately expressed the Fas antigen on the cell surface; however, all three lines were relatively resistant to cytotoxicity mediated by anti-Fas (CH-11) antibody. Pretreatment of DU145 and PC-3 with subtoxic concentrations of drugs followed by anti-Fas antibody resulted in synergistic cytotoxicity and apoptosis, whereas only an additive effect was obtained with LnCAP. Chemosensitization with drugs and anti-Fas was completely blocked by the addition of neutralizing anti-Fas antibody. The murine CTL hybridoma, PMMI, which kills only via the Fas-L pathway, was able to kill chemosensitized PC-3 and DU145 but not LnCAP cells. Furthermore, this cytotoxicity was blocked by anti-Fas neutralizing antibody. Chemosensitization of PC-3 and DU145 prostate tumor cells was not due to up-regulation of Fas-receptor antigen expression. Treatment of tumor cells with cisplatin did not down-regulate the antiapoptotic genes bcl-2, FAP-1, and c-myc. Further, there was no induction by cisplatin of Fas-L on the tumor cells, thus ruling out Fas/Fas-L-mediated autologous killing. These findings demonstrate that pretreatment of drug-resistant/CTL-resistant prostate DU145 and PC-3 tumor cells with subtoxic concentrations of certain chemotherapeutic drugs sensitizes the tumor cells to Fas-mediated cytotoxicity. These findings suggest that chemosensitization of tumor cells should optimize the response to immunotherapeutic interventions in the treatment of hormone-resistant/drug-resistant prostate cancer.
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PMID:Chemosensitization of human prostate carcinoma cell lines to anti-fas-mediated cytotoxicity and apoptosis. 981 72

The spectrum of CD30+ cutaneous lymphoproliferative disorders is characterized by the histology of a high-grade lymphoma but frequent clinical regression of skin lesions in lymphomatoid papulosis (LyP) and occasional regression in CD30+ large cell lymphomas (LCLs). A recent study shows that apoptosis may be a significant mechanism of regression of LyP (Arch Dermatol 133:828-833, 1997). Therefore, we studied expression of proteins that induce apoptosis, including CD27, CD40, CD95, and nerve growth factor receptor (NGF-R), as well as anti-apoptotic protein bcl-2 in skin lesions from 25 patients within the spectrum of CD30+ cutaneous lymphoma. Our results show consistent expression of CD95 (APO-1/Fas), but rare or absent expression of CD27, CD40, and NGF-R on tumor cells from both regressing LyP lesions and nonregressing CD30+ lymphomas. Bcl-2 was expressed at low levels in LyP and at high levels in pleomorphic CD30+ lymphomas. These results indicate that, in addition to CD30, CD95 expression is preferentially expressed at high levels in all cutaneous CD30+ lymphomas and suggest that CD95 may play a role in the regression of CD30+ skin lesions. Expression of bcl-2 appears to protect tumor cells from apoptosis in CD30+ lymphoproliferative disorders.
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PMID:Cutaneous CD30+ lymphoproliferative disorders: expression of bcl-2 and proteins of the tumor necrosis factor receptor superfamily. 982 99

Gene expression involving apoptosis in the hematopoietic system is reviewed. In normal and hematological disorders, Fas-Fas ligand and tumor necrosis factor-alpha-receptor interaction play a major role in enhancing apoptosis. On the other hand, bcl-2 or certain novel proteins (including FADD, RIP, TRADD and sentrin) prevent apoptosis. Apoptosis is involved in myelodysplastic syndrome and pathogenesis of leukemia. Expression of Fas antigen plays a role in negative regulation of hematopoiesis in the bone marrow as does interferon-gamma.
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PMID:Apoptosis-gene expression in hematopoietic system: normal and pathological conditions (Review). 985 9

Renal cell carcinoma (RCC) is the most common renal neoplasm. Despite being infiltrated by tumour infiltrating lymphocytes (TIL), these TIL are unable to control tumour growth in vivo, suggesting that the cytotoxic capacity of TIL against RCC is impaired, or that the tumour cells are resistant to killing and therefore escape detection by the immune system. It is postulated that the expression of apoptotic regulatory molecules in RCC favours tumour cell survival. The present study has therefore determined the expression of Fas (APO-1/CD95), Fas ligand (Fas L) and bcl-2 in these tumours. The expression of Fas, Fas L and bcl-2 mRNA transcripts was determined in RCC, normal kidney and peripheral blood by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), following RNA extraction and cDNA synthesis from tissues and cell samples. Transcript levels were measured by densitometry after Southern blot hybridization of PCR products with internal radio-labelled oligonucleotide probes; a densitometry score was assigned to each hybridizing DNA band and expressed as a ratio of the glyceraldehyde-3-phosphate dehydrogenase content. In peripheral blood, the expression of Fas L and bcl-2 transcripts was similar between patients and normal healthy individuals; however, Fas transcript expression was significantly down-regulated in the patients' versus normal peripheral blood (P = 0.026). Most interestingly, significantly up-regulated Fas L expression was observed in RCC compared to normal kidney (P = 0.041). In contrast, bcl-2 transcripts were well represented in normal kidney but markedly decreased in RCC (P = 0.021). The expression of Fas transcripts in normal kidney and RCC was variable. These data demonstrate elevated expression of Fas L transcripts in RCC, but the functional relevance of this remains to be investigated.
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PMID:Expression of apoptotic regulatory molecules in renal cell carcinoma: elevated expression of Fas ligand. 1010 81

Susceptibility to CD95 (Fas/APO-1)-mediated apoptosis in human glioma cells depends on CD95 expression and unknown factors that regulate signal transduction. Thus, LN-18 cells are highly sensitive to CD95 ligand (CD95L) whereas LN-229 cells require coexposure to inhibitors of RNA or protein synthesis for induction of apoptosis. Here, we report that caspase 8 and 3 activation, poly(ADP-ribose)polymerase cleavage and apoptosis are inhibited by the lipoxygenase inhibitor, nordihydroguaretic acid (NDGA), or ectopic expression of crm-A or bcl-2. CD95L-induced glioma cell apoptosis does not involve ceramide generation. Apoptosis induced by exogenous ceramide resembles CD95-mediated apoptosis in that bcl-2 is protective but differs in that NDGA and crm-A have no effect and in that cycloheximide (CHX) inhibits rather than potentiates ceramide-induced cell death. We conclude that caspase 8 and caspase 3 activation, but not ceramide generation, are required for CD95 ligand-induced apoptosis of glioma cells and that bcl-2, crm-A and NDGA all act upstream of caspases to inhibit apoptosis.
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PMID:Crm-A, bcl-2 and NDGA inhibit CD95L-induced apoptosis of malignant glioma cells at the level of caspase 8 processing. 1020 95

Death-associated protein (DAP)-kinase is a calcium/calmodulin regulated serine/threonine kinase that carries ankyrin repeats, a death domain, and is localized to the cytoskeleton. Here, we report that this kinase is involved in tumor necrosis factor (TNF)-alpha and Fas-induced apoptosis. Expression of DAP-kinase antisense RNA protected cells from killing by anti-Fas/APO-1 agonistic antibodies. Deletion of the death domain abrogated the apoptotic functions of the kinase, thus, documenting for the first time the importance of this protein domain. Overexpression of a fragment encompassing the death domain of DAP-kinase acted as a specific dominant negative mutant that protected cells from TNF-alpha, Fas, and FADD/MORT1-induced cell death. DAP-kinase apoptotic function was blocked by bcl-2 as well as by crmA and p35 inhibitors of caspases, but not by the dominant negative mutants of FADD/MORT1 or of caspase 8. Thus, it functions downstream to the receptor complex and upstream to other caspases. The multidomain structure of this serine/threonine kinase, combined with its involvement in cell death induced by several different triggers, place DAP-kinase at one of the central molecular pathways leading to apoptosis.
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PMID:DAP-kinase participates in TNF-alpha- and Fas-induced apoptosis and its function requires the death domain. 1040 66

The expression and functionality of the Fas receptor (CD95/APO-1) play an important role for the maintenance of tissue homeostasis. Various types of tumor cells have been shown to escape immune recognition by constitutive resistance to CD95-mediated apoptosis. Furthermore, several apoptosis-related proteins have been reported to influence CD95 sensitivity. We tested an unselected panel of 11 melanoma cell lines for sensitivity to CD95 and the corresponding expression of CD95, CD95L, bcl-2, bcl-x, bcl-xS, bax and FLIP proteins. Despite detection of CD95 cell-surface expression in 9 out of the 11 cell lines tested, only 3 melanoma cell lines were sensitive to anti-CD95-MAb-induced cell death. Apoptosis-related proteins CD95L, bcl-2, bcl-x, bcl-xS and bax were found to be heterogenously expressed in different melanoma cell lines tested. The susceptibility of melanoma cells to anti-CD95-MAb-mediated apoptosis was associated with low protein expression of both bcl-2 and bcl-x. The level of CD95 cell-surface expression in melanoma cells was no indicator for CD95 sensitivity. Furthermore, FLIP protein was detectable in 7 out of the 11 cell lines, but showed no correlation to CD95 sensitivity. Certain cytokines have been described as modulating the susceptibility of tumor cells to CD95-induced cell death. Since IFN-alpha was proved to be clinically efficient in melanoma therapy, we tested whether interferons have the ability to induce sensitivity to CD95 in primarily resistant melanoma cell lines. Here we show that IFN-gamma, but not IFN-alpha, is able to increase the susceptibility of sensitive cell lines and to induce CD95 sensitivity in resistant melanoma cell lines, accompanied by up-regulation of the protein expression level of CD95 and/or bcl-xS.
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PMID:Heterogenous susceptibility to CD95-induced apoptosis in melanoma cells correlates with bcl-2 and bcl-x expression and is sensitive to modulation by interferon-gamma. 1041 72

The local pattern of proinflammatory cytokine release was studied in Alzheimer disease (AD) and vascular dementia (VAD), by measuring intrathecal levels of IL-1 beta, IL-6, TNF-alpha, and its naturally occurring antagonists, soluble TNF receptors I and II. The cytokine levels were related to neuronal damage, as measured by the intrathecal tau concentration, to cerebral apoptosis assessed by levels of Fas/APO-1 and bcl-2, and to clinical variables. In vitro analysis was performed to study the effect of TNF-alpha on the production of bcl-2, an antiapoptotic factor, by human neuronal cells. Patients with both AD and VAD displayed significantly higher intrathecal levels of TNF-alpha compared to controls. In addition, patients with AD showed significantly negative correlations between the intrathecal levels of TNF-alpha and the levels of Fas/APO-1 as well as of tau protein. The level of bcl-2 in supernatants of TNF-alpha-exposed cultures of human neuronal cells was up to three times higher than in control supernatants. Our study demonstrates intrathecal production of TNF-alpha in patients with dementias, suggesting that this cytokine may have a neuroprotective role in these neurodegenerative conditions as evidenced by negative correlations between this cytokine and (i) levels of intrathecal Fas/APO-1 and (ii) levels of tau protein, both parameters closely related to brain damage. Our in vitro data suggest that TNF-alpha exerts its neuroprotective effect by stimulating neuronal cells to express bcl-2, a molecule which downregulates apoptosis.
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PMID:Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. 1047 76


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