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)

The Rho-family of small GTPases consists of essential regulators of neurite outgrowth, axonal pathfinding, and dendritic arborization. Previous work has demonstrated in non-neuronal cell types that Smurf1, an E3 ubiquitin ligase, regulates cell polarity and protrusive activity via PKCzeta-dependent recruitment to cellular protrusion sites, and subsequent ubiquitination and proteasomal degradation of RhoA. In this study, we show that Smurf1 enhances neurite outgrowth in Neuro2a neuroblastoma cells. We demonstrate that RhoA is ubiquitinated, and that Smurf1 and RhoA physically interact in vivo. Interestingly, Smurf1 overexpression in Neuro2a cells dramatically reduces RhoA protein levels during dibutyric cyclic AMP, but not retinoic acid induced neurite outgrowth. This Smurf1-dependent reduction in RhoA protein levels was abrogated using the general proteasome inhibitor MG132, suggesting that RhoA is targeted for ubiquitination and degradation via Smurf1. Together, our data suggest that localized regulation of different subsets of Rho GTPases by specific guidance signals results in an intracellular asymmetry of RhoA activity, which could regulate neurite outgrowth and guidance.
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PMID:Ubiquitination of RhoA by Smurf1 promotes neurite outgrowth. 1571 Mar 84

Transcription factor GATA-2 is expressed in a number of tissues, including hematopoietic stem and progenitor cells, and is crucial for the proliferation and survival of hematopoietic cells. To further characterize the function of GATA-2, we examined the cellular turnover mechanism of GATA-2. In P815 cells, the half-life of endogenous GATA-2 was found to be as short as 30 min after cycloheximide treatment. This short half-life was reproducible in other hematopoietic and neuroblastoma cell lines with moderate variation. We also found that ultraviolet (UV)-C irradiation markedly represses the GATA-2 protein level by facilitating the degradation process. Since treatment of the cells with the proteasome inhibitor MG132 or clasto-Lactacystin substantially abrogated the effects of cycloheximide and UV-C irradiation and increased the expression level of both endogenous and transfected GATA-2, the degradation of GATA-2 seems to occur through the proteasome pathway. Structure-function analyses with the GAL4-DNA binding domain (GBD)-GATA-2 fusion protein and GATA-2 deletion mutants suggested that the protein degradation regulatory elements of GATA-2 reside in three regions, two of which overlap with the transactivation domain. We also detected poly ubiquitinated forms of GATA-2. Taken together, these results demonstrate that GATA-2 is turned over rapidly through the ubiquitin-proteasome pathway.
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PMID:Rapid turnover of GATA-2 via ubiquitin-proteasome protein degradation pathway. 1596

Recent evidence demonstrates that the anticancer activity of betulinic acid (BetA) can be markedly increased by combination protocols, for example with chemotherapy, ionizing radiation or TRAIL. Since nuclear factor-kappaB (NF-kappaB), a key regulator of stress-induced transcriptional activation, has been implicated in mediating apoptosis resistance, we investigated the role of NF-kappaB in BetA-induced apoptosis. Here, we provide for the first time evidence that BetA activates NF-kappaB in a variety of tumor cell lines. NF-kappaB DNA-binding complexes induced by BetA consisted of p50 and p65 subunits. Nuclear translocation of p65 was also confirmed by immunofluorescence microscopy. BetA-induced NF-kappaB activation involved increased IKK activity and phosphorylation of IkappaB-alpha at serine 32/36 followed by degradation of IkappaB-alpha. Reporter assays revealed that NF-kappaB activated by BetA is transcriptionally active. Interestingly, inhibition of BetA-induced NF-kappaB activation by different chemical inhibitors (proteasome inhibitor, antioxidant, IKK inhibitor) attenuated BetA-induced apoptosis. Importantly, specific NF-kappaB inhibition by transient or stable expression of IkappaB-alpha super-repressor inhibited BetA-induced apoptosis in SH-EP neuroblastoma cells, while transient expression of IkappaB-alpha super-repressor had no influence on BetA-induced apoptosis in two other cell lines. Thus, our findings that activation of NF-kappaB by BetA promotes BetA-induced apoptosis in a cell type-specific fashion indicate that NF-kappaB inhibitors in combination with BetA would have no therapeutic benefit or could even be contraproductive in certain tumors, which has important implications for the design of BetA-based combination protocols.
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PMID:Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy. 1600 47

The proteasome inhibitor bortezomib (Velcade) was recently approved for the treatment of therapy-refractive multiple myeloma and is under investigation for numerous other types of cancer. A phase I clinical trial in paediatric patients resulted in tolerable toxicity. Since the emergence of chemoresistance represents one of the major drawbacks in cancer therapy, we investigated the influence of bortezomib on multi-drug resistant human neuroblastoma cell lines characterised by P-glycoprotein expression and p53 mutation. Nanomolar concentrations of bortezomib inhibited the cell cycle and induced apoptosis in chemosensitive as well as in chemoresistant cell lines. In vivo growth of chemosensitive and chemoresistant neuroblastoma cell lines was inhibited to a similar extent. In addition, bortezomib inhibited vessel formation in neuroblastoma xenografts. These findings and the favourable toxicity profile of bortezomib in children make it reasonable to further pursue additional development of the drug for the treatment of neuroblastoma and other paediatric solid tumours.
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PMID:Anti-cancer effects of bortezomib against chemoresistant neuroblastoma cell lines in vitro and in vivo. 1639 99

G(q/11) protein-coupled muscarinic receptors are known to regulate the release of soluble amyloid precursor protein (sAPPalpha) produced by alpha-secretase processing; however, their signaling mechanisms remain to be elucidated. It has been reported that a muscarinic agonist activates nuclear factor (NF)-kappaB, a transcription factor that has been shown to play an important role in the Alzheimer disease brain, and that NF-kappaB activation is regulated by intracellular Ca2+ level. In the present study, we investigated whether NF-kappaB activation plays a role in muscarinic receptor-mediated sAPPalpha release enhancement and contributes to a changed capacitative Ca2+ entry (CCE), which was suggested to be involved in the muscarinic receptor-mediated stimulation of sAPPalpha release. Muscarinic receptor-mediated NF-kappaB activation was confirmed by observing the translocation of the active subunit (p65) of NF-kappaB to the nucleus by the muscarinic agonist, oxotremorine M (oxoM), in SH-SY5Y neuroblastoma cells expressing muscarinic receptors that are predominantly of the M3 subtype. NF-kappaB activation and sAPPalpha release enhancement induced by oxoM were inhibited by NF-kappaB inhibitors, such as an NF-kappaB peptide inhibitor (SN50), an IkappaB alpha kinase inhibitor (BAY11-7085), a proteasome inhibitor (MG132), the inhibitor of proteasome activity and IkappaB phosphorylation, pyrrolidine dithiocarbamate, the novel NF-kappaB activation inhibitor (6-amino-4-(4-phenoxyphenylethylamino) quinazoline), and by an intracellular Ca2+ chelator (TMB-8). Furthermore, both oxoM-induced NF-kappaB activation and sAPPalpha release were antagonized by CCE inhibitors (gadolinium or SKF96365) but not by voltage-gated Ca2+-channel blockers. On the other hand, treatment of cells with NF-kappaB inhibitors (SN50, BAY11-7085, MG132, or pyrrolidine dithiocarbamate) did not inhibit muscarinic receptor-mediated CCE. These findings provide evidence for the involvement of NF-kappaB regulated by CCE in muscarinic receptor-mediated sAPPalpha release enhancement.
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PMID:Nuclear factor-kappaB activated by capacitative Ca2+ entry enhances muscarinic receptor-mediated soluble amyloid precursor protein (sAPPalpha) release in SH-SY5Y cells. 1649 Jul 83

Acute intermittent porphyria (AIP) is a neuropathic disease caused by a dominant inherited deficiency in porphobilinogen deaminase (PBGD). We investigated the expression and the degradation of the human PBGD-mutations G748A, G748C and 887insA following transfection into human SH-SY5Y neuroblastoma cells. Mutant proteins exhibited reduced protein expression compared to transfected wild-type (wt) PBGD as revealed by Western blotting. The transcription levels assessed by real-time PCR of these mutant species were identical to those of the wild type. Immuno-fluorescence microscopy revealed reduced cellular distribution of the mutated PBGDs in the cytosol and the nucleus in comparison to the wild-type PBGD. Enhanced cellular accumulation of the mutated and wild-type PBGDs was detected following inhibition of the proteasome by the inhibitors CLBL and hemin. Elevated expression of wt and mutated PBGD protein levels was either achieved by hemin or heme-arginate treatment. On the other hand, enhanced PBGD degradation was achieved by lead poisoning of ALAD in the SH-SY5Y cells concomitant with acceleration of proteasomal activity, most probably by ALAD participation in proteasomal regulation [G.G. Guo, M. Gu, J.D. Etlinger, 240-kDa proteasome inhibitor (CF-2) is identical to delta-aminolevulinic acid dehydratase. J Biol Chem 1994; 269:12399-402.] Our results suggest that the difference in expression between the wild-type and mutant proteins appears to be regulated on the level of protein degradation. In conclusion, we demonstrate that the PBGD cellular pool is controlled by the proteasome activity, which in turn is down regulated by hemin or up-regulated by Pb-ALAD.
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PMID:Proteasomal degradation regulates expression of porphobilinogen deaminase (PBGD) mutants of acute intermittent porphyria. 1693 74

The proteasome has emerged as a novel target for antineoplastic treatment of hematological malignancies and solid tumors, including those of the central nervous system. To identify cell death pathways activated in response to inhibition of the proteasome system in cancer cells, we treated human SH-SY5Y neuroblastoma cells with the selective proteasome inhibitor (PI) epoxomicin (Epoxo). Prolonged exposure to Epoxo was associated with increased levels of poly-ubiquitinylated proteins and p53, release of cytochrome c from the mitochondria, and activation of caspases. Analysis of global gene expression using high-density oligonucleotide microarrays revealed that Epoxo triggered transcriptional activation of the two Bcl-2-homology domain-3-only (BH3-only) genes p53 upregulated modulator of apoptosis (PUMA) and Bim. Subsequent studies in PUMA- and Bim-deficient cells indicated that Epoxo-induced caspase activation and apoptosis was predominantly PUMA-dependent. Further characterization of the transcriptional response to Epoxo in HCT116 human colon cancer cells demonstrated that PUMA induction was p53-dependent; with deficiency in either p53 or PUMA significantly protected HCT116 cells against Epoxo-induced apoptosis. Our data suggest that p53 activation and the transcriptional induction of its target gene PUMA play an important role in the sensitivity of cancer cells to apoptosis induced by proteasome inhibition, and imply that antineoplastic therapies with PIs might be especially useful in cancers with functional p53.
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PMID:Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway. 1698 38

Lig-8, a lignophenol derivative from bamboo lignin, potently suppresses oxidative stress-induced apoptosis. Here, we first examined in vitro whether lig-8 protects against neuronal damage induced by oxygen-glucose deprivation (OGD) followed by reoxygenation, tunicamycin [endoplasmic reticulum (ER)-stress inducer], or PSI (proteasome inhibitor). In pheochromocytoma (PC12) cell cultures, lig-8 (1 to 30 microM) concentration-dependently inhibited OGD- and tunicamycin (2 microg/ml)-induced cell deaths (significant at >/=3 microM and >/=1 microM, respectively). In human neuroblastoma (SH-SY5Y) cell culture, the PSI-induced apoptotic cell death and fusion protein accumulation (revealing reduced proteasome activity) was inhibited by lig-8 (30 microM). On the other hand, lig-8 at 30 microM alone did not affect any proteasome activity under resting conditions. In vivo, lig-8 (0.1 nmol/eye) reduced intravitreal N-methyl-D-aspartate (NMDA, 20 nmol)-induced retinal damage (decreases in retinal ganglion cells and inner plexiform layer thickness). Hence, lig-8 protects, partly by inhibiting excessive ER-stress, against neuronal damage in vitro and in vivo.
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PMID:Lig-8, a bioactive lignophenol derivative from bamboo lignin, protects against neuronal damage in vitro and in vivo. 1703 Oct 70

Lignin is a durable aromatic network polymer that is second only to cellulose in natural abundance. Lig-8, a lignophenol derivative from bamboo lignin, is a highly potent neuroprotectant. It protects human neuroblastoma cells (SH-SY5Y) from hydrogen peroxide (H2O2)-induced apoptosis by preventing caspase-3 activation via either caspase-8 or caspase-9. It exerts this antiapoptotic effect by protecting mitochondrial membrane permeability from damage by H2O2 or the peripheral benzodiazepine receptor ligand PK11195. Lig-8 has been also shown to scavenge the reactive oxygen or nitrogen species in vitro. Furthermore, lig-8 suppresses apoptosis induced by oxygen-glucose deprivation, tunicamycin (endoplasmic reticulum [ER]-stress inducer), or proteasome inhibitor in pheochromocytoma cells. In addition, in vivo, lig-8 reduced intravitreal N-methyl-D-aspartate-induced retinal damage (decreases in retinal ganglion cells and inner plexiform layer thickness) in mice. Lig-8 prevents neuronal damage partly by inhibiting excessive endoplasmic reticulum stress. In this article, we review the protective effects of lig-8 against apoptosis induced by various stimuli. Apoptosis is an active, energy-dependent process through which living cells initiate their own death. It can be induced by a variety of physiological and pharmacological stimuli. Apoptotic cell death is associated with neurodegenerative disorders such as Alzheimer, Parkinson, or Huntington disease as well as glaucoma. We believe that the elucidation of the mechanism of antiapoptotic action of lig-8 may help in finding new approaches to the treatment of neurodegenerative disorders.
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PMID:Lig-8, a highly bioactive lignophenol derivative from bamboo lignin, exhibits multifaceted neuroprotective activity. 1789 46

Bioactive natural products produced by microbes have almost limitless potential in pharmaceutical applications, and the organic synthesis of such products as lead compounds will result in the creation of new and widely useful pharmaceutical products. A program of discovery of naturally occurring bioactive microbial metabolites has been ongoing at the Kitasato Institute. We have also developed efficient, rational, and highly flexible production methods for generation of target compounds, synthesis of related compounds, elucidation of their structure-activity relationships, and the possible creation of improved bioactive compounds. In this Account, the isolation and total synthesis of naturally occurring bioactive microbial metabolites in order to create novel medicines for specific illnesses is described. This covers diseases and conditions such as atherosclerosis, Alzheimer's disease, cancer, inflammation, and osteoporosis, among others, and focuses on six specific compounds. Pyripyropenes were discovered from Aspergillus fumigatus FO-1289 through our screening of microbial metabolites that strongly inhibit acyl-CoA cholesterol acyltransferase (ACAT) in order to develop a new class of cholesterol-lowering agents. These novel polyoxygenated mixed polyketide-terpenoid (meroterpenoid) metabolites contain a fused pyridyl alpha-pyrone moiety. We carried out the first total synthesis of (+)-pyripyropene A via a flexible, concise, and highly efficient route and also clarified the structure-activity relationships. Arisugacins were discovered from Penicillium sp. FO-4259 by our screening of microbial metabolites that strongly inhibit acetylcholinesterase (AChE) in order to create novel medicines for Alzheimer's disease (AD). Arisugacins are also meroterpenoids. We have achieved the first convergent total synthesis of arisugacins A and B. Lactacystin was isolated from Streptomyces sp. OM-6519 via our screening of microbial metabolites that promote the differentiation of the neuroblastoma cell to further discover new AD medicines. Lactacystin has a novel gamma-lactam thioester structure and is also a selective and strong proteasome inhibitor. We have developed a concise approach to synthesize lactacystin designed to afford easy access to the original compound and a variety of analogs. Macrosphelides were isolated from Microsphaeropsis sp. FO-5050 from our screening of microbial metabolites that inhibit the adhesion of HL-60 cells to human umbilical vein endothelial cells (HUVEC). Macrosphelides are the first 16-membered macrotriolides. Macrosphelides prevent cell-cell adhesion by inhibiting the binding of sialyl Lewis X to E-selectin. We have accomplished the first efficient total synthesis of macrosphelides. Madindolines were isolated from Streptomyces nitrosporeus K93-0711 by our program to discover new interleukin 6 (IL-6) modulators. Madindolines are comprised of a 3a-hydroxyfuroindoline ring connected at nitrogen via a methylene bridge to a cyclopentene-1,3-dione ring. We have developed an efficient and practical total synthesis of madindolines. Madindoline A binds to gp130 selectively and inhibits IL-6 activity. Neoxaline was isolated from Aspergillus japonicus Fg-551. Neoxaline is a member of a novel class of biologically active indole alkaloids characterized by a unique indoline spiroaminal framework and binds to tubulin, which results in inhibition of tubulin polymerization. We have developed a concise stereoselective synthesis of the indoline spiroaminal framework of neoxaline.
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PMID:Efficient total synthesis of novel bioactive microbial metabolites. 1821 20


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