Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Amplification of the MYCN gene is found in a large proportion of neuroblastoma and considered as an adverse prognostic factor. To investigate the effect of ectopic MycN expression on the susceptibility of neuroblastoma cells to cytotoxic drugs we used a human neuroblastoma cell line harboring tetracycline-controlled expression of MycN. Neither conditional expression of MycN alone nor low drug concentrations triggered apoptosis. However, when acting in concert, MycN and cytotoxic drugs efficiently induced cell death. Apoptosis depended on mitochondrial permeability transition and activation of caspases, since the mitochondrion-specific inhibitor bongkrekic acid and the caspase inhibitor zVAD-fmk almost completely abrogated apoptosis. Loss of mitochondrial transmembrane potential and release of cytochrome c from mitochondria preceded activation of caspase-8 and caspase-3 and cleavage of PARP. CD95 expression was upregulated by treatment with cytotoxic drugs, while MycN cooperated with cytotoxic drugs to increase sensitivity to CD95-induced apoptosis and enhancing CD95-L expression. MycN overexpression and cytotoxic drugs also synergized to induce p53 and Bax protein expression, while Bcl-2 and Bcl-X(L) protein levels remained unchanged. Since amplification of MYCN is usually associated with a poor prognosis, these findings suggest that dysfunctions in apoptosis pathways may be a mechanism by which MycN-induced apoptosis of neuroblastoma cells is inhibited.
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PMID:MycN sensitizes neuroblastoma cells for drug-induced apoptosis. 1005 Aug 84

Fibroblast growth factor 1 (FGF1) is a multipotent factor in the development and differentiation of the central nervous system. Recent studies in PC12 cells attribute these effects to high endogenous FGF1 expression. To examine the differentiation mechanisms induced by FGF1, we performed studies in SH-SY5Y human neuroblastoma cells. We monitored the impact of FGF1 overexpression in SH-SY5Y either after addition of exogenous FGF1 and heparin or after stable transfection with the FGF1 eukaryotic expression vector. Under both conditions, the FGF1 endogenous rise caused SH-SY5Y cell differentiation with morphological changes (appearance of neuritic extensions), increased GAP-43 gene expression, decreased of N-myc gene expression, and prolonged long-term survival in serum-free media. These modifications were correlated with Bcl-2 upregulation. These results suggest that there is a link between the endogenous FGF1 signaling pathway and Bcl-2 in neuronal survival modulation.
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PMID:BCL-2 is upregulated in human SH-SY5Y neuroblastoma cells differentiated by overexpression of fibroblast growth factor 1. 1032 57

We identified betulinic acid (BetA) as a new cytotoxic agent active against neuroectodermal tumor cells including neuroblastoma, medulloblastoma, glioblastoma and Ewing's sarcoma cells representing the most common solid tumors of childhood. BetA induced apoptosis independent of wild-type p53 protein and accumulation of death-inducing ligand/receptor systems such as CD95. BetA had a direct effect on mitochondria resulting in the release of soluble apoptogenic factors such as cytochrome c or AIF from mitochondria into the cytosol where they induced activation of caspases. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-XL that blocked loss of the mitochondrial membrane potential and cytochrome c release from mitochondria conferred resistance to BetA at the level of mitochondrial dysfunction, protease activation and nuclear fragmentation. Neuroblastoma cells resistant to CD95- or doxorubicin-triggered apoptosis remained sensitive to treatment with BetA suggesting that BetA may bypass some forms of resistance. Moreover, BetA exhibited potent antitumor activity on primary tumor cell cultures from all neuroblastoma (4/4), all medulloblastoma (4/4) and most glioblastoma patients (20/24) ex vivo. These findings suggest that BetA may be a promising new agent in the treatment of neuroectodermal tumors in vivo.
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PMID:Betulinic acid: a new chemotherapeutic agent in the treatment of neuroectodermal tumors. 1047 70

Human catecholaminergic neuroblastoma cells (SH-SY5Y) have been widely used in different neurochemical investigations. Quite often these cells are induced to differentiation by various agents, such as staurosporine and retinoic acid. Interestingly, even though both staurosporine and retinoic acid induce similar morphological differentiation in SH-SY5Y cells, we found that these two groups of differentiated cells exhibited opposite vulnerability to harmful chemicals and physical insults. In the present study, cisplatin, 5-fluorouracil (5-FU), N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), 6-hydroxydopamine (6-OHDA), and gamma-radiation were used to assess the tolerance of the differentiated cells. Cell viability was determined by 3-(4,5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Staurosporine-treated SH-SY5Y cells were more sensitive to these toxic insults than the untreated controls. In contrast, retinoic acid-treated cells became more resistant to the same treatments. The expression of the proteins of the protooncogene Bcl-2 and the tumor suppressor gene p53 following staurosporine or retinoic acid treatment was assessed by Western blot and immunocytochemistry. Retinoic acid increased Bcl-2 and decreased p53 levels, whereas staurosporine decreased Bcl-2 and increased p53 levels. The opposite alteration of Bcl-2 (anti-apoptotic) and p53 (apoptotic) contents in SH-SY5Y cells with retinoic acid and staurosporine are attributed to the changes in cell vulnerability. These observations also indicate that caution should be taken when chemically induced differentiated neuroblastoma cells are to be used as an in vitro model for studying neuronal survival.
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PMID:Differential effects of staurosporine and retinoic acid on the vulnerability of the SH-SY5Y neuroblastoma cells: involvement of bcl-2 and p53 proteins. 1051 16

The expression, cellular localization, and activation of the NF-kappaB/Rel transcription factors are altered during neuronal differentiation, but the significance is unclear. Here we investigate the requirement for NF-kappaB/Rel proteins in neuronal differentiation. SH-SY5Y neuroblastoma cells were induced to differentiate with retinoic acid (RA) or 12-O-tetradecanoylphorbol 13-acetate (TPA), and differentiation was demonstrated by morphological criteria and the enhanced expression of Bcl-2. NF-kappaB was transiently activated after the addition of the differentiation inducers before the morphological signs of differentiation and the enhanced Bcl-2 synthesis. The onset of NF-kappaB activation coincided with a significant reduction in the amount of only one of four NF-kappaB-inhibitory proteins examined (I-kappaBbeta). In contrast, NF-kappaB activation and the reduction in I-kappaBbeta failed to occur in SH-SY5Y cells transformed with I-kappaBalphaM, a dominant-negative inhibitor of NF-kappaB/Rel proteins. These I-kappaBalphaM-expressing cells failed to differentiate into neuronal cell types when treated with RA or TPA, and the increased Bcl-2 synthesis was blocked. Therefore, NF-kappaB/Rel proteins are required for neuronal differentiation of SH-SY5Y neuroblastoma cells.
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PMID:NF-kappaB/Rel proteins are required for neuronal differentiation of SH-SY5Y neuroblastoma cells. 1052 6

Methylmercury (MeHg) is known to interfere with cell cycle progression by disruption of microtubules. The relationship between the changes in cell cycle and the induction of apoptosis caused by MeHg was investigated in cultured mammalian cells. MeHg caused nuclear fragmentation and DNA ladder formation in rat pheochromocytoma (PC12) and mouse neuroblastoma cells exposed to MeHg. Flow cytometric analysis revealed that the occurrence of apoptosis was preceded by the accumulation of cells in G2/M after MeHg treatment. Exposure to colchicine, a well-characterized mitotic inhibitor, also caused G2/M-phase arrest followed by the appearance of apoptotic cells. These results suggest that G2/M-phase arrest through the disruption of microtubules is an important event in the development of apoptosis by MeHg. MeHg treatment led to G2/M-phase arrest followed by apoptosis in nonneuronal HeLa cells also. Bcl-2 was phosphorylated by MeHg treatment in HeLa cells but not in PC12 cells; however, p53 expression was not changed in either cell line. Thus, MeHg induces apoptosis via a p53-independent pathway in both cell lines, however, different pathways may be activated after the disruption of microtubules in PC12 and HeLa cells.
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PMID:The involvement of microtubular disruption in methylmercury-induced apoptosis in neuronal and nonneuronal cell lines. 1054 62

We have investigated the role of mitochondrial Ca(2+) (Ca(m)) homeostasis in cell survival. Disruption of Ca(m) homeostasis via depletion of the mitochondrial Ca(2+) store was the earliest event that occurred during staurosporine-induced apoptosis in neuroblastoma cells (SH-SY5Y). The decrease of Ca(m) preceded activation of the caspase cascade and DNA fragmentation. Overexpression of the anti-apoptosis protein Bcl-2 led to increased Ca(m) load, increased mitochondrial membrane potential (DeltaPsi(m)), and inhibition of staurosporine-induced apoptosis. On the other hand, ectopic expression of the pro-apoptotic protein Bik led to decreased Ca(m) load and decreased DeltaPsi(m). Inhibition of calcium uptake into mitochondria by ruthenium red induced a dose-dependent apoptosis as determined by nuclear staining and DNA ladder assay. Similarly, reducing the Ca(m) load by lowering the extracellular calcium concentration also led to apoptosis. We suggest that the anti-apoptotic effect of Bcl-2 is related to its ability to maintain a threshold level of Ca(m) and DeltaPsi(m) while the pro-apoptotic protein Bik has the opposite effect. Furthermore, both ER and mitochondrial Ca(2+) stores are important, and the depletion of either one will result in apoptosis. Thus, our results, for the first time, provide evidence that the maintenance of Ca(m) homeostasis is essential for cell survival.
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PMID:Modulation of mitochondrial Ca(2+) homeostasis by Bcl-2. 1055 1

We correlated the adenine nucleotide (AN) levels and energy charge (EC) at the end of a transient oxidative exposure to the delayed death of neuronal cells. When wild-type (WT) or Bcl-2-overexpressing (BCL-2) human neuroblastoma cells (Paju) were exposed to 250 microM H(2)O(2) for 60 min, the EC of WT cells was unchanged, but that of BCL-2 cells decreased from 0.91 +/- 0.03 to 0.67 +/- 0.02. Depletion of ANs was significantly greater in BCL-2 (66.7 +/- 2%) than in WT (38.8 +/- 2%) cells. Proliferation of both lines decreased, averaging 63 +/- 17% of control by 48 h. Exposure to 5 mM H(2)O(2) caused no further change in ANs in BCL-2 cells but in WT cells decreased the EC to 0.45 +/- 0.08 and depleted ANs to 41 +/- 9% of control; after 24 h, WT cells became pyknotic and showed DNA fragmentation but no chromatin condensation, whereas BCL-2 cells died by delayed necrosis. After 10 mM H(2)O(2), EC dropped to 0.15 +/- 0.1, and both lines were acutely killed. The EC after an oxidative insult correlated well with further growth of both cell lines. A significant decline in EC led to delayed death. Bcl-2 did not protect against the fall in EC or AN depletion, but, although survival was not improved, the mechanism of death appeared to be different.
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PMID:Correlation of oxidant-induced acute ATP depletion with delayed cell death in human neuroblastoma cells. 1056 80

Nitric oxide (NO) challenge to human neuroblastoma cells (SH-SY5Y) ultimately results in apoptosis. Tumor suppressor protein p53 and cell cycle inhibitor p21 accumulate as an early sign of S-nitrosoglutathione-mediated toxicity. Cytochrome c release from mitochondria and caspase 3 activation also occurred. Cells transfected with either wild type (WT) or mutant (G93A) Cu, Zn-superoxide dismutase (Cu,Zn-SOD) produced comparable amounts of nitrite/nitrate but showed different degree of apoptosis. G93A cells were the most affected and WT cells the most protected; however, Cu, Zn-SOD content of these two cell lines was 2-fold the SH-SY5Y cells under both resting and treated conditions. We linked decreased susceptibility of the WT cells to higher and more stable Bcl-2 and decreased reactive oxygen species. Conversely, we linked G93A susceptibility to increased reactive oxygen species production since simultaneous administration of S-nitrosoglutathione and copper chelators protects from apoptosis. Furthermore, G93A cells showed a significant decrease of Bcl-2 expression and, as target of NO-derived radicals, showed lower cytochrome c oxidase activity. These results demonstrate that resistance to NO-mediated apoptosis is strictly related to the level and integrity of Cu,Zn-SOD and that the balance between reactive nitrogen and reactive oxygen species regulates neuroblastoma apoptosis.
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PMID:Cu,Zn-superoxide dismutase-dependent apoptosis induced by nitric oxide in neuronal cells. 1067 49

Arsenic trioxide-induced apoptosis was identified by morphological change and nucleosomal DNA fragmentation in hematopoietic malignant cells and neuroblastoma cells. Arsenic trioxide directly induced apoptosis in the acute promyelocytic cell line NB4 cells at a low dose of 1 microM, whereas all-trans-retinoic acid caused the cells to differentiate and finally induced apoptosis. In addition to the involvement of caspase 3 in arsenic trioxide-induced apoptosis of NB4 cells, the activation of caspase 8 was also shown to be involved by Western blot analysis or by apoptosis inhibition assay using caspase 8 inhibitor Ac-IETD-CHO. The down-regulation of Bcl-2 protein was shown in arsenic trioxide-treated pre-apoptotic and early apoptotic mouse B-cell line LyH7 cells, which overexpress Bcl-2 protein, by the studies of Western blot and immunoelectron microscopy. Arsenic trioxide also induced apoptosis in the majority of neuroblastomas cell lines. The arsenic-induced apoptosis in neuroblastoma cell lines was mediated by the activation of caspase 3 in all cases tested. In regard to the intracellular content of reduced glutathione in various neuroblastoma cell lines, the level in the cells sensitive to arsenic trioxide was under 40 nmol/mg protein, but the cells having more than 40 nmol/mg protein did not undergo apoptosis. N-acetylcysteine protected neuroblastoma cells from arsenic-induced apoptosis. Therefore, the intracellular glutathione content may be a good indicator of application of arsenic trioxide for various kinds of cancer cells. Our results raise the possibility that arsenic trioxide will be effective even against a solid tumor such as neuroblastoma and warrants clinical trials for patients with other kinds of tumors not only by systemic therapy but also using local therapy.
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PMID:Arsenic-induced apoptosis in malignant cells in vitro. 1072 69


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