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 vitro experiments revealed that the scrapie prion protein, PrP(Sc), as well as the PrP fragment PrP106-126, and the HIV-1 coat protein gp120 induce apoptosis of rat cortical neurons. The toxic effect displayed by PrP and gp120 could be blocked by NMDA receptor antagonists. Treatment of neuronal cells with PrP106-126 resulted in a drop of intracellular glutathione level and changes in the level of Bcl-2. Evidence is presented that gp120 causes an activation of phospholipase A2, resulting in the increased release of arachidonic acid, which may in turn sensitize the NMDA receptor.
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PMID:Mechanisms of prionSc- and HIV-1 gp120 induced neuronal cell death. 974 29

The scrapie prion protein, PrP(Sc), as well as its peptide fragment, PrP106-126, are toxic on neuronal cells, resulting in cell death by an apoptotic, rather than necrotic mechanism. The apoptotic process of neuronal cells induced by prion protein supports diagnosis and offers potential targets for therapeutic intervention of the prion diseases. Among the cerebrospinal fluid (CSF) proteins, which may serve as markers of neuronal cell death associated with prion diseases, the 14-3-3 protein(s) turned out to be the most promising one. A new sensitive assay allows the detection of even small changes in the normally low levels of these proteins. In vitro, the toxic effects displayed by PrP(Sc) and its peptide fragment can be blocked by antagonists of N-methyl-D-aspartate (NMDA) receptor channels, like Memantine. Also Flupirtine, a non-opiod analgesic drug, which is already in clinical use, was found to display in vitro a strong cytoprotective effect on neurons treated with PrP(Sc) or PrP106-126. This drug acts like a NMDA receptor antagonists, but does not bind to the receptor. Clinical trials on prion diseases with Flupirtine are in progress. Flupirtine was found to enhance the intracellular levels of the antiapoptotic protein Bcl-2 and the antioxidative agent glutathione (GSH). Due to its favourable pharmacokinetic profile, Flupirtine is considered to be a promising drug to prevent neuronal death in Creutzfeldt-Jakob disease (CJD) and other neurodegenerative disorders occurring with age, e.g. Alzheimer's disease.
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PMID:Novel approaches in diagnosis and therapy of Creutzfeldt-Jakob disease. 1099 19

Apoptotic neuronal cell death is a hallmark of prion diseases. The apoptotic process in neuronal cells is thought to be caused by the scrapie prion protein, PrPSc, and can be experimentally induced by its peptide fragment, PrP106-126. This process is a target for potential drugs to combat prion disease or to ameliorate its symptoms. Flupirtine (Katadolon), a pyridine derivative that is in clinical use as a nonopioid analgesic, has a potent cytoprotective effect, at concentrations above 1 microg/mL, on neuronal cells treated with PrP(Sc) or PrP106-126. This drug acts as an N-methyl-D-aspartate (NMDA) antagonist, but does not bind to NMDA receptors. Flupirtine normalizes the level of intracellular glutathione and increases the expression of the antiapoptotic Bcl-2 protein in neuronal cells exposed to prion protein. In view of its favorable pharmacokinetic profile, flupirtine is the first drug to be considered as a potential treatment for Creutzfeldt-Jakob disease, the human form of prion diseases. Clinical trials are underway.
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PMID:Neuroprotective effect of flupirtine in prion disease. 1253 84

Many uncertainties remain regarding the physiological function of the prion protein PrP and the consequences of its conversion into the pathological scrapie isoform in prion diseases. Here, we show for the first time that different signal transduction pathways are involved in neurite outgrowth and neuronal survival elicited by PrP in cell culture of primary neurons. These pathways include the nonreceptor Src-related family member p59(Fyn), PI3 kinase/Akt, cAMP-dependent protein kinase A, and MAP kinase. Regulation of Bcl-2 and Bax expression also correlates with the survival effect elicited by PrP. The combined results, along with our observation that PrP carries the recognition molecule-related HNK-1 carbohydrate, argue strongly for a role of the molecule in neural recognition by interacting with yet unknown heterophilic neuronal receptors, as shown by comparison of neurite outgrowth from neurons of PrP-deficient and wild-type mice.
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PMID:Prion protein as trans-interacting partner for neurons is involved in neurite outgrowth and neuronal survival. 1267 32

Prion diseases are characterized by accumulation of misfolded prion protein (PrP(Sc)), and neuronal death by apoptosis. Here we show that nanomolar concentrations of purified PrP(Sc) from mouse scrapie brain induce apoptosis of N2A neuroblastoma cells. PrP(Sc) toxicity was associated with an increase of intracellular calcium released from endoplasmic reticulum (ER) and up-regulation of several ER chaperones. Caspase-12 activation was detected in cells treated with PrP(Sc), and cellular death was inhibited by overexpression of a catalytic mutant of caspase-12 or an ER-targeted Bcl-2 chimeric protein. Scrapie-infected N2A cells were more susceptible to ER-stress and to PrP(Sc) toxicity than non-infected cells. In scrapie-infected mice a correlation between caspase-12 activation and neuronal loss was observed in histological and biochemical analyses of different brain areas. The extent of prion replication was closely correlated with the up-regulation of ER-stress chaperone proteins. Similar results were observed in humans affected with sporadic and variant Creutzfeldt-Jakob disease, implicating for the first time the caspase-12 dependent pathway in a neurodegenerative disease in vivo, and thus offering novel potential targets for the treatment of prion disorders.
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PMID:Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. 1453 16

In our previous work, cellular prion protein (PrPc) was identified as an upregulated gene in adriamycin-resistant gastric carcinoma cell line SGC7901/ADR compared to its parental cell line SGC7901. Here we investigate the expression of PrPc in gastric cancer and whether it was involved in multidrug resistance (MDR) of gastric cancer. We demonstrated that PrPc was ubiquitously expressed in gastric cancer cell lines and tissues. PrPc conferred resistance of both P-glycoprotein (P-gp)-related and P-gp-nonrelated drugs on SGC7901, which was accompanied by decreased accumulation and increased releasing amount of adriamycin in PrPc-overexpressing cell line. Inhibition of PrPc expression by antisense or RNAi technology could partially reverse multidrug-resistant phenotype of SGC7901/ADR. PrPc significantly upregulated the expression of the classical MDR-related molecule P-gp but not multidrug resistance associated protein and glutathione S-transferase pi. The PrPc-induced MDR could be partially reversed by P-gp inhibitor verapamil. PrPc could also suppress adriamycin-induced apoptosis and alter the expression of Bcl-2 and Bax, which might be another pathway contributing to PrPc-related MDR. The further study of the biological functions of PrPc may be helpful for understanding the mechanisms of occurrence and development of clinical gastric carcinoma and PrPc-related MDR and developing possible strategies to treat gastric cancer.
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PMID:Overexpression and significance of prion protein in gastric cancer and multidrug-resistant gastric carcinoma cell line SGC7901/ADR. 1538 5

Cellular prion protein (PrP(C)), a glycosylphosphatidylinositol-anchored membrane protein, was found in our lab to be widely expressed in gastric cancer cell lines. In order to evaluate its biological significance in human gastric cancer, we investigated its expression in a large series of gastric tissue samples (n = 124) by immuno histochemical staining with the monoclonal antibody 3F4. Compared with normal tissues, gastric adenocarcinoma showed increased PrP(C) expression, correlated with the histopathological differentiation (according to the WHO and Lauren classifications) and tumor progression (as documented by pTNM staging). To better understand the underlying mechanism, we introduced the PrP(C) and two pairs of RNAi into the poorly differentiated gastric cancer cell line AGS and found that PrP(C) suppressed ROS and slowed down apoptosis in transfected cells. Further study proved that the apoptosis-related protein Bcl-2 was upregulated whereas p53 and Bax were downregulated in the PrP(C)-transfected cells. A reverse effect was observed in PrP(C) siRNA-transfected cells. These results strongly suggested that PrP(C) might play a role as an effective antiapoptotic protein through Bcl-2-dependent apoptotic pathways in gastric cancer cells. Further study into the mechanism of these relationships might enrich the knowledge of PrP, better our understanding of the nature of gastric carcinoma, and further develop possible strategies to block or reverse the development of gastric carcinoma.
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PMID:Overexpression of PrPC and its antiapoptosis function in gastric cancer. 1658 85

Although apoptosis has been implicated in the neuronal loss observed in prion diseases, the participation of apoptosis-related factors, like the Bcl-2 family of proteins, is still not clear. Moreover, there are conflicting data concerning the major role of apoptosis in the neuropathology associated with transmissible spongiform encephalopathies. Many studies have been developed in vitro or in experimentally infected animal models but, at present, little is known about this process in natural spontaneous and acquired prion diseases. In this work, the implication of Bax and Bcl-2 has been investigated by the analysis of their expression and protein distribution in medulla oblongata of naturally scrapie-infected sheep. Moreover, their spatial relationship with PrP(Sc) deposition, neuronal vacuolation and neuropil spongiosis has also been analysed as well as the possible induction of neuronal apoptosis in this model. Real Time RT-PCR showed overexpression of the pro-apoptotic gene Bax in scrapie medullas, and immunohistochemistry confirmed its accumulation. No variation of Bcl-2 was observed at the level of gene expression or protein production. Bax distribution, PrP(Sc) deposition, neuronal vacuolation and spongiosis were quantified in different medulla oblongata nuclei and their spatial relationship was evaluated. Bax staining showed a positive correlation with prion deposition, suggesting that this factor is involved in prion neurotoxicity in our natural model. Despite Bax overexpression, neuronal apoptosis was revealed neither by TUNEL nor by immunohistochemical detection of the activated form of caspase-3. This lack of apoptosis could be attributed to the relatively low number of neurons in this area or to the existence of neuroprotective mechanisms in medulla oblongata motor neurons.
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PMID:Correlation between Bax overexpression and prion deposition in medulla oblongata from natural scrapie without evidence of apoptosis. 1680 9

Prnp knockout mice that overexpress an amino-truncated form of PrPc (deltaPrP) are ataxic and display cerebellar cell loss and premature death. Studies on the molecular and intracellular events that trigger cell death in these mutants may contribute to elucidate the functions of PrPc and to the design of treatments for prion disease. Here we examined the effects of Bcl-2 overexpression in neurons on the development of the neurological syndrome and cerebellar pathology of deltaPrP. We show that deltaPrP overexpression activates the stress-associated kinases ERK1-2 in reactive astroglia, p38 and the phosphorylation of p53, which leads to the death of cerebellar neurons in mutant mice. We found that the expression of deltaPrP in cell lines expressing very low levels of PrPc strongly induces the activation of apoptotic pathways, thereby leading to caspase-3 activation and cell death, which can be prevented by coexpressing Bcl-2. Finally, we corroborate in vivo that neuronal-directed Bcl-2 overexpression in deltaPrP mice (deltaPrP Bcl-2) markedly reduces caspase-3 activation, glial activation, and neuronal cell death in cerebellum by improving locomotor deficits and life expectancy.
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PMID:Bcl-2 overexpression delays caspase-3 activation and rescues cerebellar degeneration in prion-deficient mice that overexpress amino-terminally truncated prion. 1749 93

Although the function of cellular prion protein (PrPc) and the pathogenesis of prion diseases have been widely described, the mechanisms are not fully clarified. In this study, increases of the portion of non-glycosylated prion protein deposited in the hamster brains infected with scrapie strain 263K were described. To elucidate the pathological role of glycosylation profile of PrP, wild type human PrP (HuPrP) and two genetic engineering generated non-glycosylated PrP mutants (N181Q/N197Q and T183A/T199A) were transiently expressed in human astrocytoma cell line SF126. The results revealed that expressions of non-glycosylated PrP induced significantly more apoptosis cells than that of wild type PrP. It illustrated that Bcl-2 proteins might be involved in the apoptosis pathway of non-glycosylated PrPs. Our data highlights that removal of glycosylation of prion protein provokes cells apoptosis.
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PMID:Removal of the glycosylation of prion protein provokes apoptosis in SF126. 1792 98


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