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

---

Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transglutaminase type 2 (TG2; also known as G(h)) is a multifunctional protein involved in diverse cellular processes. It has two well characterized enzyme activities: receptor-stimulated signaling that requires GTP binding and calcium-activated transamidation or cross-linking that is inhibited by GTP. In addition to the GDP binding residues identified from the human TG2 crystal structure (Liu, S., Cerione, R. A., and Clardy, J. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 2743-2747), we have previously implicated Ser171 in GTP binding, as binding is lost with glutamate substitution (Iismaa, S. E., Wu, M.-J., Nanda, N., Church, W. B., and Graham, R. M. (2000) J. Biol. Chem. 275, 18259-18265). Here, we have shown that alanine substitution of homologous residues in rat TG2 (Phe174 in the core domain or Arg476, Arg478, or Arg579 in barrel 1) does not affect TG activity but reduces or abolishes GTP binding and GTPgammaS inhibition of TG activity in vitro, indicating that these residues are important in GTP binding. Alanine substitution of Ser171 does not impair GTP binding, indicating this residue does not interact directly with GTP. Arg579 is particularly important for GTP binding, as isothermal titration calorimetry demonstrated a 100-fold reduction in GTP binding affinity by the R579A mutant. Unlike wild-type TG2 or its S171E or F174A mutants, which are sensitive to both trypsin and mu-calpain digestion, R579A is inherently more resistant to mu-calpain, but not trypsin, digestion, indicating reduced accessibility and/or flexibility of this mutant in the region of the calpain cleavage site(s). Basal TG activity of intact R579A stable SH-SY5Y neuroblastoma cell transfectants was slightly increased relative to wild-type transfectants and, in contrast to the TG activity of the latter, was further stimulated by muscarinic receptor-activated calcium mobilization. Thus, loss of GTP binding sensitizes TG2 to intracellular calcium concentrations. These findings are consistent with the notion that intracellularly, under physiological conditions, TG2 is maintained largely as a latent enzyme, its calcium-activated cross-linking activity being suppressed allosterically by guanine nucleotide binding.
...
PMID:Mutation of a critical arginine in the GTP-binding site of transglutaminase 2 disinhibits intracellular cross-linking activity. 1652 28

Calpains represent a superfamily of Ca2+-activated cysteine-proteases, which are important mediators of apoptosis and necrosis. In the brain, m-calpain and micro-calpain, the two ubiquitous calpain-isoforms, are strongly activated in neurones after an excitotoxic Ca2+ influx occurring, for example, during cerebral ischemia. Because oestrogen and its receptors (ERalpha/ERbeta) can exert neuroprotective activity, we investigated their influence on expression of calpains and their endogenous inhibitor, calpastatin. We found that ectopic expression of ERalpha in human neuroblastoma SK-N-MC cells led to a ligand-independent constitutive down-regulation of m-calpain accompanied by an up-regulation of micro-calpain expression. Up-regulation of micro-calpain was reversed in the presence of oestrogen, which, in turn, could be blocked by co-treatment with the oestrogen-receptor antagonist ICI 182,780. Expression of calpastatin was not altered, either in the absence or in the presence of oestrogen. Additional studies revealed that ERalpha-expressing cells exhibited decreased calpain enzymatic activity and increased survival when cells were exposed to the Ca2+ ionophore, ionomycin. Since all investigated effects could be observed exclusively in the presence of ERalpha, but not ERbeta, and since the effects are reduced when ERalpha and ERbeta are co-expressed, our data suggest a novel ER subtype-specific neuroprotective action by repressing calpain expression and calpain activity under conditions of a massive Ca2+ influx.
...
PMID:Oestrogen receptor subtype-specific repression of calpain expression and calpain enzymatic activity in neuronal cells--implications for neuroprotection against Ca-mediated excitotoxicity. 1652 85

Apoptosis-inducing factor (AIF) is a bifunctional NADH oxidase involved in mitochondrial respiration and caspase-independent apoptosis. Three alternatively spliced mRNA isoforms of AIF have been identified previously: AIF, AIF-exB, and AIFsh. Here, we report the cloning and the biochemical characterization of a new isoform named AIF short 2 (AIFsh2). AIFsh2 transcript includes a previously unknown exon placed between exons 9 and 10 of AIF. The resulting AIFsh2 protein, which localizes in mitochondria, corresponds to the oxidoreductase domain of AIF. In this way, AIFsh2 exhibits similar NADH oxidase activity to AIF and generates reactive oxygen species. Like AIF, AIFsh2 is released from mitochondria to cytosol after an apoptotic insult in a calpain or cathepsin-dependent manner. However, in contrast to AIF, AIFsh2 does not induce nuclear apoptosis. Thus, it seems that the reactive oxygen species produced by the oxidoreductase domain of AIF/AIFsh2 are not important for AIF-dependent nuclear apoptosis. In addition, we demonstrate that the AIFsh2 mRNA is absent in normal brain tissue, whereas it is expressed in neuroblastoma-derived cells, suggesting a different regulation in normal and transformed cells from the brain lineage. Together, our results reveal that AIF yields an original and independent genetic regulation of the two AIF functions. This is an important issue to understand the physiological role of this protein.
...
PMID:Identification and characterization of AIFsh2, a mitochondrial apoptosis-inducing factor (AIF) isoform with NADH oxidase activity. 1664 25

Microtubule-stabilizing and -destabilizing proteins play a crucial role in regulating the dynamic instability of microtubules during neuronal development and synaptic transmission. The microtubule-destabilizing protein SCG10 is a neuron-specific protein implicated in neurite outgrowth. The SCG10 protein is significantly reduced in mature neurons, suggesting that its expression is developmentally regulated. In contrast, the microtubule-stabilizing protein tau is expressed in mature neurons and its function is essential for the maintenance of neuronal polarity and neuronal survival. Thus, the establishment and maintenance of neuronal polarity may down-regulate the protein level/function of SCG10. In this report, we show that treatment of PC12 cells and neuroblastoma cells with the microtubule-stabilizing drug Taxol induced a rapid degradation of the SCG10 protein. Consistently, overexpression of tau protein in neuroblastoma cells also induced a reduction in SCG10 protein levels. Calpain inhibitor MDL-28170, but not caspase inhibitors, blocked a significant decrease in SCG10 protein levels. Collectively, these results indicate that tau overexpression and Taxol treatment induced a calpain-dependent degradation of the microtubule-destabilizing protein SCG10. The results provide evidence for the existence of an intracellular mechanism involved in the regulation of SCG10 upon microtubule stabilization.
...
PMID:Taxol and tau overexpression induced calpain-dependent degradation of the microtubule-destabilizing protein SCG10. 1682 11

Cell death is a common feature observed in neurodegenerative disorders, and is often associated with calpain activation and overproduction of reactive oxygen species (ROS). This study investigated the use of calpain inhibitors and antioxidants in combination to protect cells against necrosis. Maitotoxin (MTX), which induces a massive influx of calcium, was used to provoke neuronal cell death. This toxin increased, in a concentration-dependent manner, both calpain activity and ROS formation. Calpain inhibitors or antioxidants inhibited MTX-induced necrosis only marginally (below 20%), whereas their association protected against cell death by 40-66% in a synergistic manner. BN 82204, which possesses both calpain-cathepsin L inhibitory and antioxidant properties, and its acetylated pro-drug BN 82270, totally protected cells at 100 microm. The pro-drug BN 82270, which had better cell penetration, was twice as effective as the active principle BN 82204 in protecting glioma C6 or neuroblastoma SHSY5Y cells against death. These results suggest the potential therapeutic relevance of using a single molecule with multiple activities (cysteine protease inhibitor/antioxidant), and warrant further in vivo investigations in models of neuronal disorders.
...
PMID:Calpain inhibitors and antioxidants act synergistically to prevent cell necrosis: effects of the novel dual inhibitors (cysteine protease inhibitor and antioxidant) BN 82204 and its pro-drug BN 82270. 1689 84

Calpains are calcium- and thiol-dependent proteases whose overactivation and degradation of various substrates have been implicated in a number of diseases and conditions such as cardiovascular dysfunction and ischemic stroke. With increasing evidence for calpain's role in cellular damage, the development of calpain inhibitors continues to be an important objective. Previously, we identified a highly specific calcium-dependent, calpain interacting peptide L-S-E-A-L, that showed homology to domains A and C of the only known endogenous inhibitor of calpains, calpastatin. This suggested that LSEAL had a calpain inhibitory function and synthetic LSEAL inhibited calpain I and II proteolysis of two calpain substrates, tau and alpha-synuclein. In the present study, we demonstrate that synthetic LSEAL is membrane permeable and is a potent inhibitor in two established models of calpain-mediated cell death using primary rat cortical neurons and SH-SY5Y neuroblastoma cells. In addition, we show that LSEAL inhibits calpain activity towards protein substrates as detected by an antibody to a calpain-specific breakdown product of spectrin. Taken together, these results suggest that LSEAL may represent a novel calpastatin mimetic with the potential for benefit in conditions of increased calpain activity such as stroke, traumatic brain injury or heart attack.
...
PMID:Inhibition of calpain-mediated cell death by a novel peptide inhibitor. 1695 7

Neuroblastoma is the most common extracranial solid tumor in children causing death at pre-school age, as no cure has yet been developed. We investigated the proteolytic mechanisms for apoptosis in human malignant (N-type) neuroblastoma SH-SY5Y cells following exposure to flavonoids such as apigenin (APG), (-)-epigallocatechin (EGC), (-)-epigallocatechin-3-gallate (EGCG) and genistein (GST). We found decrease in viability of SH-SY5Y cells with an increase in dose of APG, EGC, EGCG and GST. Predominantly apoptosis occurred following exposure of SH-SY5Y cells to 50 microM APG, 50 microM EGC, 50 microM EGCG and 100 microM GST for 24 hr. Apoptosis was associated with increases in intracellular free [Ca(2+)] and Bax:Bcl-2 ratio, mitochondrial release of cytochrome c and activation of caspase-9, calpain and caspase-3. Induction of apoptosis with APG and GST showed activation of caspase-12 as well. Activation of caspase-3 could cleave the inhibitor-of-caspase-activated DNase (ICAD) to release and translocate caspase-3-activated DNase (CAD) to the nucleus. Activation of caspase-8 cleaved Bid to truncated Bid (tBid) in cells treated with EGC and EGCG. EGC and EGCG induced apoptosis with caspase-8 activation and mitochondria-mediated pathway, whereas APG and GST caused apoptosis via an increase in intracellular free [Ca(2+)] with calpain activation and mitochondria-mediated pathway. Activation of different proteases for cell death was confirmed using caspase-8 inhibitor II, calpeptin (calpain inhibitor), caspase-9 inhibitor I and caspase-3 inhibitor IV. Thus, plant-derived flavonoids cause cell death with activation of proteolytic activities of calpain and caspases in SH-SY5Y cells, and therefore serve as potential therapeutic agents for controlling the growth of neuroblastoma.
...
PMID:Mechanism of apoptosis with the involvement of calpain and caspase cascades in human malignant neuroblastoma SH-SY5Y cells exposed to flavonoids. 1698 47

Among marine sessile organisms, sponges (Porifera) are the major producers of bioactive secondary metabolites that defend them against predators and competitors and are used to interfere with the pathogenesis of many human diseases. Some of these biological active metabolites are able to influence cell survival and death, modifying the activity of several enzymes involved in these cellular processes. These natural compounds show a potential anticancer activity but the mechanism of this action is largely unknown. In this study, we investigated the effects of two Mediterranean sponges, Agelas oroides and Petrosia ficiformis on the viability of human neuroblastoma cells. Upon treatment with the methanolic extract of Petrosia ficiformis, a marked cytotoxic effect was observed at any concentration or time of exposure. In contrast, a time- and dose-dependent effect was monitored for Agelas oroides that induced the development of apoptotic features and ROS production in LAN5 cells. These events were suppressed by calpeptin or zVAD and by vitamin C suggesting that the cell death caused by Agelas oroides was calpain- and caspase-dependent and of oxidative nature. Comet assay showed that this methanolic extract was not able to produce a genotoxic effect. Future studies will be applied to investigate the effect of isolated bioactive compounds from crude extract of this sponge which are potentially useful for cancer therapeutics.
...
PMID:Effects of Agelas oroides and Petrosia ficiformis crude extracts on human neuroblastoma cell survival. 1714 25

Malignant (N-type) neuroblastoma continues to defy current chemotherapeutic regimens. We tested the garlic compounds diallyl sulfide (DAS) and diallyl disulfide (DADS) for induction of apoptosis in human malignant neuroblastoma SH-SY5Y cells. Viability of human primary neurons was unaffected after 24 h treatment with 50 and 100 microM DAS and 50 microM DADS but slightly affected with 100 microM DADS. Treatment with 50 and 100 microM DAS or DADS significantly decreased viability in SH-SY5Y cells. Wright staining showed morphological features of apoptosis in SH-SY5Y cells treated with 50 and 100 microM DAS or DADS for 24 h. ApopTag assay demonstrated DNA fragmentation in apoptotic cells. Apoptosis was associated with an increase in [Ca(2+)](i), increase in Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, increase in cytosolic Smac/Diablo, and down regulation of inhibitor-of-apoptosis proteins and nuclear factor kappa B (NFkappaB). Activation of caspase-9 and caspase-3 indicated involvement of intrinsic pathway of apoptosis. Calpain and caspase-3 activities produced 145 kD spectrin break down product (SBDP) and 120 kD SBDP, respectively. Also, caspase-3 activity cleaved inhibitor of caspase-activated DNase (ICAD). Results strongly suggested that the garlic compounds DAS and DADS suppressed anti-apoptotic factors and activated calpain and intrinsic caspase cascade for apoptosis in SH-SY5Y cells.
...
PMID:Garlic compounds induced calpain and intrinsic caspase cascade for apoptosis in human malignant neuroblastoma SH-SY5Y cells. 1721 50

Arsenic trioxide (As(2)O(3)) is toxic to multidrug-resistant neuroblastoma cells in vivo and in vitro. In neuroblastoma, As(2)O(3) does not exert its cell death-promoting effects via a classical apoptotic pathway. A death mechanism involving proteolytic cleavage of Bax to a p18 form seems to be of importance, because inhibition of Bax cleavage coincides with diminished cell death. As existing models of cell death implicate Bax in the intrinsic apoptotic pathway, triggering death after Bax translocation to the mitochondria, we investigated the cellular localization of p18 Bax by subcellular fractionation. After As(2)O(3) treatment, p18 Bax was only present in nuclei-enriched, mitochondria-depleted fractions. Cytoplasmic p21 Bax levels decreased, whereas total (p21 and p18) nuclear Bax increased. Overexpressed p21 Bax localized to the cytoplasm and nuclei, whereas overexpressed p18 Bax localized to extra-nuclear structures only. The inability of overexpressed p18 Bax to locate to the nucleus, and the As(2)O(3)-induced reduction of p21 Bax in the cytosol, suggest an As(2)O(3)-induced mechanism where p18 Bax gets cleaved and 'trapped' in the nucleus. This model is strengthened by the observation that calpain, the protease responsible for p18 Bax generation, is present in the nuclei, and that nuclear calpain is induced by increasing As(2)O(3) and Ca(2+) levels.
...
PMID:Arsenic trioxide-induced neuroblastoma cell death is accompanied by proteolytic activation of nuclear Bax. 1740 72


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---