Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fenretinide-induced apoptosis of neuroectodermal tumour cells is mediated through generation of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, mitochondrial cytochrome c release and caspase activation. The present study describes the requirement of the BH3-domain only protein Noxa for this process and its regulation by p53. Noxa expression was induced by fenretinide in neuroblastoma and melanoma cells, including those with mutated p53, and this induction was abolished by antioxidants. Knockdown of p53 by RNA interference (RNAi) demonstrated upregulation of Noxa protein levels in response to fenretinide was p53-independent, although evidence suggested that Noxa may be transcriptionally regulated by p53. The ER stress-inducing agent thapsigargin also induced p53-independent Noxa expression. Conversely, Noxa transcription in response to the chemotherapeutic agents cisplatin or temozolomide was inhibited by p53 knockdown. Apoptosis in response to cisplatin or temozolomide was also inhibited by abrogation of p53 expression yet apoptosis in response to fenretinide or thapsigargin was unaffected. RNAi-mediated down-regulation of Noxa inhibited apoptosis in response to fenretinide or thapsigargin, whereas apoptosis induced by cisplatin or temozolomide was unaffected. These data demonstrate the importance of Noxa induction in determining the apoptotic response to fenretinide and emphasise the role of Noxa in p53-independent apoptosis.
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PMID:Role of Noxa in p53-independent fenretinide-induced apoptosis of neuroectodermal tumours. 1721 84

Boron isotope ratios are homogeneous in volcanic glasses of oceanic island basalts [-9.9 +/- 1.3 per mil, relative to standard NBS 951 (defined by the National Bureau of Standards)], whereas mid-oceanic ridge basalts (MORBs) and back-arc basin basalts (BABBs) show generally higher and more variable ratios. Melts that have assimilated even small amounts of altered basaltic crust show significant variations in the boron isotope ratios. Assimilation may thus account for the higher boron ratios of MORBs and BABBs. A budget of boron between mantle and crust implies that the primitive mantle had a boron isotope ratio of -10 +/- 2 per mil and that this ratio was not fractionated significantly during the differentiation of the mantle.
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PMID:Primitive boron isotope composition of the mantle. 1784 Dec 61

Structural relaxation in silicate glasses with different (p,T) histories was experimentally examined by differential scanning calorimetry and measurements of molar volume under ambient pressure. Temperature and pressure-dependent rates of changes in molar volume and generation of excess enthalpy were determined for sodium trisilicate, soda lime silicate, and sodium borosilicate (NBS) compositions. From the derived data, Prigogine-Defay ratios are calculated and discussed. Changes of excess enthalpy are governed mainly by changes in short-range structure, as is shown for NBS where boron coordination is highly sensitive to pressure. For all three glasses, it is shown how the relaxation functions that underlie volume, enthalpy, and structural relaxation decouple for changes in cooling rates and pressure of freezing, respectively. The magnitude of the divergence between enthalpy and volume may be related to differences in structural sensitivity to changes in the (p,V,T,t) space on different length scales. The findings suggest that the Prigogine-Defay ratio is related to the magnitude of the discussed decoupling effect.
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PMID:Molar volume, excess enthalpy, and Prigogine-Defay ratio of some silicate glasses with different (P,T) histories. 1794 69

Mitochondrial alterations have been associated with the cytotoxic effect of 6-hydroxydopamine (6-OHDA), a widely used toxin to study Parkinson's disease. In previous work, we have demonstrated that 6-OHDA increases mitochondrial membrane permeability leading to cytochrome c release, but the precise mechanisms involved in this process remain unknown. Herein we studied the mechanism of increased mitochondrial permeability of SH-SY5Y neuroblastoma cells in response to 6-OHDA. Cytochrome c release induced by 6-OHDA occurred, in both SH-SY5Y cells and primary cultures, in the absence of mitochondrial swelling or a decrease in mitochondrial calcein fluorescence, suggesting little involvement of the mitochondrial permeability transition pore in this process. In contrast, 6-OHDA-induced cell death was associated with a significant translocation of the pro-apoptotic Bax protein from the cytosol to mitochondria and with a significant induction of the BH3-only protein PUMA. Experiments in mouse embryonic fibroblasts deficient in Bax or PUMA demonstrated a role for both proteins in 6-OHDA-induced apoptosis. Although 6-OHDA elevated both total and nuclear p53 protein levels, activation of p53 was not essential for subsequent cell death. In contrast, we found that p38 mitogen-activated protein kinase (MAPK) was activated early during 6-OHDA-induced apoptosis, and that treatment with the p38 MAPK inhibitor SKF86002 potently inhibited PUMA induction, green fluorescent protein-Bax redistribution and apoptosis in response to 6-OHDA. These data demonstrate a critical involvement of p38 MAPK, PUMA, and Bax in 6-OHDA-induced apoptosis.
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PMID:6-Hydroxydopamine activates the mitochondrial apoptosis pathway through p38 MAPK-mediated, p53-independent activation of Bax and PUMA. 1799 28

BH3-only proteins couple diverse stress signals to the evolutionarily conserved mitochondrial apoptosis pathway. Previously, we reported that the activation of the BH3-only protein p53-up-regulated mediator of apoptosis (Puma) was necessary and sufficient for endoplasmic reticulum (ER) stress- and proteasome inhibition-induced apoptosis in neuroblastoma and other cancer cells. Defects in protein quality control have also been suggested to be a key event in ALS, a fatal neurodegenerative condition characterized by motoneuron degeneration. Using the SOD1(G93A) mouse model as well as human post mortem samples from ALS patients, we show evidence for increased ER stress and defects in protein degradation in motoneurons during disease progression. Before symptom onset, we detected a significant up-regulation of Puma in motoneurons of SOD1(G93A) mice. Genetic deletion of puma significantly improved motoneuron survival and delayed disease onset and motor dysfunction in SOD1(G93A) mice. However, it had no significant effect on lifespan, suggesting that other ER stress-related cell-death proteins or other factors, such as excitotoxicity, necrosis, or inflammatory injury, may contribute at later disease stages. Indeed, further experiments using cultured motoneurons revealed that genetic deletion of puma protected motoneurons against ER stress-induced apoptosis but showed no effect against excitotoxic injury. These findings demonstrate that a single BH3-only protein, the ER stress-associated protein Puma, plays an important role during the early stages of chronic neurodegeneration in vivo.
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PMID:Deletion of the BH3-only protein puma protects motoneurons from ER stress-induced apoptosis and delays motoneuron loss in ALS mice. 1807 68

Boron nitride nanotubes (BNNTs) have unique physical properties, which can be exploited in the biomedical field. Hence, the surprising lack of reported studies on their biocompatibility and interactions with living cells, addressed by the present paper which deals the results of such an investigation based on 72 h culture of human neuroblastoma cell line (SH-SY5Y) in the presence of an aqueous suspension of polyethyleneimine (PEI)-coated BNNTs. BNNTs conjugated with fluorescent markers (quantum dots) are employed to enable tracking of their uptake by living cells. The results demonstrate good cytocompatibility together with unequivocal BNNT cellular uptake by an energy-dependent endocytic process.
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PMID:Cytocompatibility, interactions, and uptake of polyethyleneimine-coated boron nitride nanotubes by living cells: confirmation of their potential for biomedical applications. 1851 59

While in the last years applications of carbon nanotubes in the field of biotechnology have been largely proposed, biomedical applications of boron nitride nanotubes (BNNTs) are yet totally unexplored. BNNTs have very interesting physical properties that should be exploited in the biomedical field. At this date, studies on their biocompatibility are completely missing and the first issue behind this investigation is the dispersion of BNNTs in aqueous solutions. In this paper the authors propose, for the first time, a technique for obtaining BNNT stable dispersions suitable for biological applications, based on polyethyleneimine (PEI) water solutions. Based on authors' knowledge, in vitro testing performed on human neuroblastoma cell line (SH-SY5Y) is the first study of interaction between BNNTs and living material. Experimental results showed a satisfactory cell viability up to a concentration of 5.0 microg/ml PEI-BNNTs in the cell culture medium.
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PMID:Preparation of boron nitride nanotubes aqueous dispersions for biological applications. 1920 87

Accumulating evidence suggests that zinc (Zn2+) contributes to neuronal death in pathologic states such as ischemia. p53-upregulated modulator of apoptosis (PUMA), which is a BH3-only protein, is known to promote apoptosis through a tumor suppressor p53-dependent and -independent mechanism. In this study, we examined the effect of Zn2+ on the induction of the PUMA gene in human neuroblastoma SH-SY5Y cells. The expression of PUMA was induced by Zn2+ in a dose- and time-dependent manner. A reporter assay revealed that Zn2+ activated the PUMA promoter. In addition, the mutation of the p53 binding site in the PUMA promoter region reduced promoter activation by Zn2+. These findings suggest that p53 participates in Zn2+-induced PUMA expression. Furthermore, we also demonstrated here that Zn2+ stimulates the phosphorylation of ERK and that the MEK-ERK pathway inhibitor, U0126, suppressed Zn2+-induced PUMA expression. Taken together, these results indicate that Zn2+ regulates the induction of PUMA through p53 and ERK pathways.
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PMID:Zinc induces expression of the BH3-only protein PUMA through p53 and ERK pathways in SH-SY5Y neuroblastoma cells. 1924 Nov 61

Cancer arises through genetic alterations that improve cellular fitness and increase autonomy. These alterations, in addition to those invoked by genomic, metabolic and mechanical stressors, activate checkpoints that cancer cells must circumvent, including mitochondrial apoptosis. Thus, there is selective pressure to bypass apoptotic signaling in cancer cells, and this process is largely governed by Bcl-2 homology (BH) proteins. Given the primacy of the mitochondrial apoptosis checkpoint, it is surprising that the integrity of the apoptotic machinery is preserved in most cancers. Instead, it is the threshold for activating cell death that is elevated in cancer cells to provide a survival bias. Therapeutic opportunities are emerging as the roles for BH proteins are elucidated in normal and cancer cells. This review discusses small-molecule BH3 mimetics for the restoration of cancer-cell sensitivity to apoptotic stressors. Neuroblastoma, a lethal childhood tumor in which emergent therapy resistance is common, is presented to provide a model for the rational integration of BH3 mimetics into the clinic.
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PMID:Small-molecule BH3 mimetics to antagonize Bcl-2-homolog survival functions in cancer. 1951 40

Bcl-2 family proteins regulate mitochondrial apoptosis downstream of diverse stressors. Cancer cells frequently deregulate Bcl-2 proteins leading to chemoresistance. We have optimized a platform for solid tumors in which Bcl-2 family resistance patterns are inferred. Functional mitochondria were isolated from neuroblastoma (NB) cell lines, exposed to distinct BH3-domain peptides, and assayed for cytochrome c release. Such BH3 profiles revealed three patterns of cytochrome c response. A subset had a dominant NoxaBH3 response implying Mcl1 dependence. These cells were more sensitive to small molecules that antagonize Mcl1 (AT-101) than those that antagonize Bcl-2, Bcl-xL and Bcl-w (ABT-737). A second subset had a dominant BikBH3 response, implying a Bcl-xL/-w dependence, and was exquisitely sensitive to ABT-737 (IC(50) <200 nM). Finally, most NB cell lines derived at relapse were relatively resistant to pro-death BH3 peptides and Bcl-2 antagonists. Our findings define heterogeneity for apoptosis resistance in NB, help triage emerging Bcl-2 antagonists for clinical use, and provide a platform for studies to characterize post-therapy resistance mechanisms for NB and other solid tumors.
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PMID:BH3 response profiles from neuroblastoma mitochondria predict activity of small molecule Bcl-2 family antagonists. 1989 70


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