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)

Bax is a pro-apoptotic member of the Bcl-2 family that plays an important role in neuronal apoptosis. However, the results are controversial, especially regarding its function in the apoptosis involved in prion diseases. This work analyzes the gene expression and protein distribution of Bax in the central nervous systems of sheep naturally infected with scrapie. Gene expression profiling, obtained by means of real-time RT-PCR analysis, has shown a significant over-expression of this pro-apoptotic factor in medulla oblongata and diencephalon, whereas its expression was stable in cerebellum and prefrontal cortex. Immunohistochemistry confirmed the expression results and extended the investigation to 13 different regions. A high degree of variability was found in Bax immunoreactivity, mainly in the scrapie group, which also corresponded to the degree of PrP(Sc) deposition. Despite this variability, qualitative differences were found between scrapie and control groups. Intraneuronal reactivity for Bax was mainly observed in the spinal cord, brain stem, hypothalamus, and colicullus of scrapie animals, whereas controls displayed immunoreactivity almost exclusively in the neuropile. Moreover, a significant positive correlation was observed between Bax and prion deposition. Despite Bax over-expression, the activated form of caspase-3 was never observed in neurons showing apoptotic-like morphology. In contrast, activated caspase-3 staining appeared as cytoplasmic granules in apparently healthy neurons. We conclude that apoptosis either occurs in an extremely low number of neurons or neuroprotective mechanisms arrest the mitochondrial pathway after Bax induction.
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PMID:Differential expression and protein distribution of Bax in natural scrapie. 1794 98

We investigated the relationship between the resistance to the proapoptotic action of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and cellular prion protein (PrPc) function, using the TRAIL-sensitive MCF-7 human breast adenocarcinoma cell line and two TRAIL-resistant sublines: 2101 and MCF-7/ADR. All of the cell lines tested expressed TRAIL-R1 and TRAIL-R2. TRAIL decoy receptors were not detected, suggesting that the resistance of 2101 and MCF-7/ADR cells, strongly expressing PrPc, to TRAIL-mediated cell death was independent from the expression of TRAIL receptors and death-inducing signaling complex formation. Down-regulation of PrPc by small interfering RNA increased the sensitivity of Adriamycin- and TRAIL-resistant cells to TRAIL, but not to epirubicin/Adriamycin. TRAIL-mediated apoptosis in PrPc knocked-down cells was associated with caspase processing, Bid cleavage, and Mcl-1 degradation. In addition, an increased sensitivity of apoptosis-resistant cells to TRAIL after PrPc silencing was not associated with the increased recruitment of receptors and intracellular signaling molecule to the death-inducing signaling complex. Bcl-2 expression was substantially decreased after PrPc knock-down but the levels of Bcl-X(L) and Mcl-1 were not affected. The down-regulation of Bcl-2 was concomitant with Bax delocalization. Our findings support the notion that silencing of PrPc facilitates the activation of proapoptotic Bax by down-regulation of Bcl-2 expression, thereby abolishing the resistance of breast cancer cells to TRAIL-induced apoptosis.
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PMID:Silencing of prion protein sensitizes breast adriamycin-resistant carcinoma cells to TRAIL-mediated cell death. 1800 36

In this study we analysed the effect of Bcl-2 on the cytotoxicity induced by the amyloid-beta (Abeta(25-35)) and prion (PrP(106-126)) peptides by using GT1-7puro and GT1-7bcl-2 (overexpressing the anti-apoptotic protein Bcl-2) neural cells. Exposure to Abeta(25-35) (1-5 microM) and PrP(106-126) (25 microM) caused a decrease in cell viability, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. These data were correlated with Abeta(25-35) and PrP(106-126)-induced activation of caspase-9, which is linked to the mitochondrial death pathway, and the activation of the effector caspase-3, suggesting cell death by apoptosis. Furthermore, Bcl-2 overexpression protected from loss of cell viability and caspase-9 and -3 activation induced by Abeta(25-35) and PrP(106-126), showing that Bcl-2 is neuroprotective against apoptotic cell death caused by amyloidogenic peptides.
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PMID:Bcl-2 overexpression protects against amyloid-beta and prion toxicity in GT1-7 neural cells. 1805 55

Doppel (Dpl) is a recently identified prion (PrP)-like protein due to the structural and biochemical similarities, however, its natural function and pathogenic role in neurodegenerative diseases remains unclear. To investigate the possible pathogenic pathway of Dpl and its structural analog for cell apoptosis, mammalian expressing recombinant plasmids containing human PRND gene encoding the full-length Dpl and a truncated human PRNP gene deleting the sequences encoding the peptide from aa 32 to 121 (PrPDelta32-121) were generated. MTT assays showed the cell viabilities of the human neuroblastoma cell line SH-SY5Y receiving Dpl and PrPDelta32-121 expressing plasmids were remarkably lower. Obvious apoptosis phenomena were observed to be associated with the cells transient expressing Dpl and PrPDelta32-121, including reduced mitochondrial transmembrane potential (psim), decreased pro-caspase-3 quantity, more numbers of annexin V- and annexin V/PI-double-stained cells and depressed Bcl-2 level. Moreover, we also found that the Dpl- and PrPDelta32-121-induced cytotoxicities and relevant apoptotic events in SH-SY5Y cells could be fully antagonized by co-expression of the human full-length PrP. These data highly indicate that cytotoxicity induced by the expression of Dpl and truncated PrP in neural derived cells are closely related with the apoptosis process, probably triggering the mitochondrial pathway. It also implies that the cell-benefit activity of the full-length PrP may result from its anti-apoptosis capacity.
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PMID:Transient expressions of doppel and its structural analog prionDelta32-121 in SH-SY5Y cells caused cytotoxicity possibly by triggering similar apoptosis pathway. 1972 51

Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal isoform of the prion protein PrP(Sc). Human prion protein fragment, PrP (106-126) (prion protein peptide 106-126), may contain most of the pathological features associated with PrP(Sc). Hypoxic conditions elicit cellular responses adaptively designed to improve cell survival and have an important role in the process of cell survival. We investigate the effects of hypoxia on PrP (106-126)-induced apoptosis in the present study. Human neuroblastoma and glioblastoma cells were incubated with varied doses of PrP (106-126) under both normoxic or hypoxic conditions, in order to determine the regulatory effects of hypoxia on PrP (106-126)-induced apoptosis. The results indicate that hypoxia protects neuronal cells against PrP (106-126)-induced cell death by activating the Akt signal, which is inactivated by prion proteins, and inhibiting PrP (106-126)-induced caspase 3 activation. Low oxygen conditions increase the Bcl-2 protein, which is associated with anti-apoptotic signals, and recover the PrP (106-126)-induced reduction in mitochondrial transmembrane potential. This study demonstrates that hypoxia inhibits PrP (106-126)-induced neuron cell death by regulating Akt and Akt-related signaling, and it also suggests that prion-related neuronal damage and disease may be regulated by hypoxia or by hypoxic-inducing genes.
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PMID:Hypoxia protects neuronal cells from human prion protein fragment-induced apoptosis. 1991 74

Octarepeats region sequence is one of the most important characteristics of PrP topology. To explore the mechanism of deleted and inserted octarepeats mutants PrP-caused apoptosis, wild-type PrP (PrP-PG5), and PrP with deleted octarepeats (PrP-PG0) and with four (PrP-PG9) and seven (PrP-PG12) extra octarepeats were transiently induced into SH-SY5Y cell. The results indicated PrP-PG9 and PrP-PG12 mainly retained in fraction of cytoplasm, while PrP-PG5 and PrP-PG0 presented both in cell membrane and cytoplasm. Cells expressing PrP-PG9 and PrP-PG12 were sensitive to endoplasmic reticulum (ER) stimuli, tunicamycin, and brefeldin A. ER-stress-related proteins, Grp94, XBP1, TRAF2, and CHOP, were significantly increased in cells expressing PrP-PG9 and PrP-PG12, while Grp78 increased markedly 12 h and pro-caspase-12 decreased sharply 20 h post-transfection. It indicates that expressions of PrP mutants with inserted octarepeats cause ER stress and lead to cell apoptosis lately. Meanwhile, cellular Cytochrome C increased and Bcl-2 decreased obviously in cells expressing PrP-PG0, indicating triggering a mitochondrial-related apoptosis. These data highlight that PrP mutants in region of octarepeats may undergo different pathways to trigger cell apoptosis, in which PrPs with inserted octarepeats via ER stress and PrP mutant without octarepeats via mitochondrial-related pathway.
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PMID:Human prion protein mutants with deleted and inserted octarepeats undergo different pathways to trigger cell apoptosis. 2052 96

Since 2004 cases of atypical bovine spongiform encephalopathy (BSE) in older cattle are recorded on the basis of aberrant glycoprofiles of prion protein resistant to proteolysis (PrP(res)). The nature of those types of PrP(res) is still not fully understood but the epidemiological data indicate that their occurrence is rare. Hitherto, most BSE cases were studied on the basis of the features of pathological form of prion protein (PrP(Sc)) or lesions observed in the gray matter of the brain. Here we propose the gene expression profiling as a method to characterize and distinguish BSE types. Thus, the aim of the study was to compare the activity of some genes which are known to play a role in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Significant differences in the expression level of the selected genes in the brain stem were observed for 7 out of 11 genes tested when the results for BSE affected and healthy control animals were compared. Significant up-regulation of caspase 3, Bax and 14-3-3 protein encoding genes was apparent in the obex of all BSE affected cattle regardless of the prion type. Significant and unique to BSE H-type up-regulation was detected in prion and SOD1 genes, while BSE C-type was characterized by higher Bcl-2 and Fyn gene expression levels in respect to other BSE types and control animals. Different gene expression profiles of bovine brains infected with classical and atypical BSE indicate possible different pathogenesis or origin of the disease.
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PMID:Comparison of mRNA expression levels of selected genes in the brain stem of cattle naturally infected with classical and atypical BSE. 2065 96

The prion diseases are neurodegenerative disorders characterized by the conversion of the PrPc (normal cellular prion) to the PrPsc (misfolded isoform). The accumulation of PrPsc within the central nervous system (CNS) leads to neurocytotoxicity by increasing oxidative stress. In addition, many neurodegenerative disorders including prion, Parkinson's and Alzheimer's diseases may be regulated by cholesterol homeostasis. The effects of cholesterol balance on prion protein-mediated neurotoxicity and ROS (reactive oxygen species) generation were the focus of this study. Cholesterol treatment inhibited PrP (106-126)-induced neuronal cell death and ROS generation in SH-SY5Y neuroblastoma cells. In addition, the PrP (106-126)-mediated increase of p53, p-p38, p-ERK and the decrease of Bcl-2 were blocked by cholesterol treatment. These results indicated that cellular cholesterol enrichment is a key regulator of PrP-106-126-mediated oxidative stress and neurotoxicity. Taken together, the results of this study suggest that modulation of cellular cholesterol appears to prevent the neuronal cell death caused by prion peptides.
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PMID:Cellular cholesterol enrichment prevents prion peptide-induced neuron cell damages. 2087

Autophagy plays an important role in targeting cellular proteins, protein aggregates and organelles for degradation for cell survival. Autophagy dysfunction has been extensively described in neurodegenerative conditions linked to protein misfolding and aggregation. However, the role of autophagy in the prion disease process is unclear. Here, we show that when expressed in mouse neuroblastoma N2a cells, cytoplasmic PrP (cyPrP) aggregates lead to endoplasmic reticulum stress (ER stress), activation of reticulon 3 (RTN3), impairment of ubiquitin-proteasome system (UPS), induction of autophagy and apoptosis. RTN3 belongs to the reticulon family with the highest expression in the brain and RTN3 is often activated under ER stress. To assess the function of RTN3 in pathological conditions involving cyPrP protein misfolding, we knocked down the expression of RTN3 in cyPrP-transfected cells; unexpectedly, the inhibition of expression of RTN3 enhances the induction of autophagy resulted from cyPrP aggregates, and the process is mediated by the enhanced interaction between Bcl-2 and Beclin1 promoted by RTN3, which enhances Bcl-2-mediated inhibition of Beclin 1-dependent autophagy. Furthermore, down-regulation of RTN3 promoted the clearance of cyPrP aggregates, allowed the activity of the UPS to resume and alleviated ER stress; ultimately, apoptosis due to the cyPrP aggregates was inhibited. Together, these data suggest that RTN3 negatively regulates autophagy to block the clearance of cyPrP aggregates and provide a clue regarding the potential to induce autophagy for the treatment of prion disease and other neurodegenerative diseases such as Parkinson disease (PD), Alzheimer disease (AD) and Huntington disease (HD).
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PMID:Reticulon 3 attenuates the clearance of cytosolic prion aggregates via inhibiting autophagy. 2111 7

Prion diseases are infectious neurodegenerative disorders characterized by the conversion of the cellular prion protein (PrPc) to the misfolded isoform (PrPsc). Prion peptide PrP 106-126 [PrP (106-126)] shares many physiological properties with PrPsc; it is neurotoxic in vitro and in vivo. PrP (106-126) induces neurotoxicity by the overexpression of PrPc and activation of the mitogen-activated protein (ERK1/2). Aspirin, an anti-inflammatory drug, is a known ERK inhibitor and prevents neurodegenerative disorders including prion diseases. The influence of aspirin treatment on prion protein-mediated neurotoxicity and expression of PrPc were the focus of this study. Cell viability and apoptosis were assessed by crystal violet staining and the TUNEL and DNA fragmentation assays. Apoptosis-associated protein expression of PrPc, p-53, p-ERK1/2, p-p38, Bcl-2 and cleaved-caspase-3 was examined by Western blotting and immunocytochemistry. Aspirin treatment inhibited PrP (106-126)-induced neuronal cell death in SH-SY5Y neuroblastoma cells. In addition, the PrP (106-126)-mediated increase of p-p38, p53, cleaved-caspase-3 and decrease of Bcl-2 expressions were blocked by aspirin and the ERK inhibitor, PR98059. Furthermore, we showed that the PrP (106-126)-mediated increase of PrPc and p-ERK1/2 were inhibited by PD98059 and aspirin. Taken together, these results demonstrate that ERK1/2 is a key modulator of the protective effect of aspirin on PrP-106-126-mediated cellular prion protein overexpression and neurotoxicity and also suggest that aspirin may prevent neuron cell damages caused by the prion peptide.
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PMID:Prion peptide-mediated cellular prion protein overexpression and neuronal cell death can be blocked by aspirin treatment. 2134 12


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