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)

Using the yeast two-hybrid system, complementary DNA clones were isolated from a HeLa cell library encoding proteins that interacted with p52shc. One of these clones encoded the non-catalytic, COOH-terminal half of the cytosolic protein tyrosine phosphatase PTP-PEST. Expression of truncated forms of p52shc in the two-hybrid system revealed that the amino-terminal half of p52shc was sufficient for interaction with PTP-PEST. The p52 and p66 forms of Shc, but not the p46 form, bound to a glutathione S-transferase fusion protein containing the region of PTP-PEST isolated from the two-hybrid screen. Similarly, when HeLa cell lysates were immunoprecipitated with PTP-PEST antiserum, p52shc and p66shc proteins, but not p46shc, co-precipitated. Shc-PTP-PEST complex formation was stimulated 6-8-fold by the protein kinase C activator phorbol 12-myristate 13-acetate, while epidermal growth factor and serum had no effect. Phorbol 12-myristate 13-acetate also stimulated phosphorylation of p52shc and p66shc. The muscarinic agonist carbachol (also an activator of protein kinase C) stimulated complex formation 3-5-fold in SH-SY5Y neuroblastoma cells. These results suggest a role for PTP-PEST in G protein receptor signaling and in cross-talk between G protein receptor and tyrosine kinase receptor pathways.
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PMID:Activators of protein kinase C stimulate association of Shc and the PEST tyrosine phosphatase. 792 14

Nerve growth factor (NGF), essential for differentiation and survival of sympathetic neurons is suggested to play a role in differentiation or regression of neuroblastoma. Expression of mRNA for the trk protooncogene, encoding a tyrosine kinase receptor essential for functional NGF signal transduction, and mRNA for the low affinity NGF receptor (LNGFR) was examined in 45 neuroblastomas and 3 benign ganglioneuromas using Northern blot analysis. Expression of trk mRNA and LNGFR mRNA correlated with young age, favorable clinical stages, and absence of N-myc amplification. All children (n = 19) with neuroblastomas coexpressing mRNA for trk and LNGFR are alive 8-84 months from diagnosis, regardless of age and stage. In contrast, no child (n = 15) with tumor lacking trk mRNA is alive without disease. Three subsets of patients were distinguished, one favorable (trk+, LNGFR+, n = 19, 100% survival probability), one intermediate (trk+, LNGFR-, n = 11, 62.3% survival probability), and one unfavorable (trk-, LNGFR +/-, n = 15, 0% survival probability, P < 0.001). In widespread neuroblastoma stage IVS prone to spontaneous regression, three tumors coexpressing trk and LNGFR mRNAs regressed after no or minimal therapy while the remaining tumor expressing trk but not LNGFR mRNA progressed to a fatal outcome. It is concluded that neuroblastomas coexpressing mRNA for both NGF receptor subtypes are favorable tumors likely to differentiate or regress spontaneously or respond to conventional therapy. It is further hypothesized that loss of functional NGF receptors is an important step in tumorigenesis of undifferentiated malignant childhood neuroblastoma. For these unfavorable tumors current therapy remains futile and first-line innovative therapy is justified.
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PMID:Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis. 848 6

Childhood neuroblastoma tumours of the sympathetic nervous system show a remarkable clinical heterogeneity ranging from spontaneous regression to unfavourable outcome despite intensive therapy. Favourable neuroblastomas often express high levels of trkA mRNA, encoding the tyrosine kinase receptor for nerve growth factor. We have investigated mRNA expression for the neurotrophin receptor trkC in 23 primary neuroblastomas using a sensitive RNAase protection assay. TrkC expression was detected in 19 of these tumours at highly variable levels with a 300-fold difference between the highest and lowest values. Significantly higher levels of trkC mRNA were found in tumours from patients with favourable features such as low age (P < 0.012), favourable tumour stage (P < 0.012) and favourable prognosis (P < 0.05). Children with intermediate or high trkC mRNA expression had better prognosis compared with those with low or undetectable levels (83.3% vs 20%, P = 0.005). Further characterisation of trkC mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR) showed that mRNA encoding the full-length cytoplasmic tyrosine kinase domain of the receptor was only expressed in a subset of favourable tumours. These data show that favourable neuroblastomas may express the full trkC receptor while advanced tumours, in particular MYCN-amplified neuroblastoma, seem to either express no trkC or truncated trkC receptors of as yet unknown biological function. These data are suggestive of a role for trkC and its preferred ligand neutotrophin-3, NT-3, in neuroblastoma differentiation and/or regression.
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PMID:Expression of mRNA for the neurotrophin receptor trkC in neuroblastomas with favourable tumour stage and good prognosis. 879 81

G protein-coupled receptors activate phospholipase C (PLC)-beta isoforms by the alpha or beta gamma subunits of G proteins, whereas growth-factor receptors activate PLC-gamma isoforms by phosphorylating tyrosine residues of the enzyme. As a common substrate for PLC enzymes, phosphatidylinositol 4,5-bisphosphate [Ptdins(4,5)P2] may play a pivotal role in the regulation of cellular PLC activity. Because small-molecular-weight G proteins have been implicated in the synthesis of Ptdins(4,5)P2, we studied the effect of Clostridium difficile toxin B, which glucosylates and thereby inactivates small G proteins of the Rho family, on receptor-stimulated PLC activity. We report here that in N1E-115 neuroblastoma cells, stimulation of inositol phosphate formation by the G protein-coupled receptor agonists bradykinin and lysophosphatidic acid and by the tyrosine kinase receptor agonist platelet-derived growth factor is largely attenuated by toxin B treatment. Furthermore, inositol phosphate production stimulated by the stable GTP analog guanosine 5'-O-(3-thio)-triphosphate in permeabilized N1E-115 cells was inhibited by C3 exoenzyme, which specifically inactivates Rho proteins. The inhibition by toxin B was apparently not caused by its effect on the cytoskeleton. In addition, the level of platelet-derived growth factor receptors, which was studied with immunoblotting, was unaffected by toxin B. Using exogenous Ptdlns(4,5)P2 as PLC substrate, it was found that the intrinsic enzymatic activity of PLC activated either by Ca2+ or by guanosine 5'-O-(3-thio)triphosphate was not altered by toxin B. However, toxin B decreased strongly, by up to 80%, the cellular level of Ptdins(4,5)P2 in a concentration-dependent manner, without changing those of phosphatidylinositol and phosphatidylinositol 4-phosphate. These results, together with the recent finding that Rho family proteins can regulate phosphatidylinositol 4-phosphate 5-kinase activity, demonstrate that Rho proteins are presumably important regulators of Ptdins(4,5)P2 synthesis and, thereby, play an integral role in the regulation of cellular signaling by PLC enzymes.
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PMID:Inhibition by toxin B of inositol phosphate formation induced by G protein-coupled and tyrosine kinase receptors in N1E-115 neuroblastoma cells: involvement of Rho proteins. 886 31

Expression level of trkA tyrosine kinase receptor for nerve growth factor is a major prognostic determinant of neuroblastoma, suggesting that defective trkA-mediated signaling is responsible for the tumorigenesis of this childhood malignancy. We investigated the biologic effect of trkA, with special reference to its effect on insulin-like growth factor-II (IGF-II) expression, in SK-N-AS human neuroblastoma cells transfected with human trkA cDNA. Nerve growth factor treatment of trkA-transfected cells promoted growth and changed the morphologic phenotype into a substrate-adherent, flatter phenotype (S-type), and down-regulated the mRNA expression of IGF-II. The effects on both growth and the morphologic differentiation of SK-N-AS cells differed significantly from those of previous studies, and implied that trkA effects can be diverse, depending on the phenotype of the individual neuroblastoma cells. Immunohistochemical screening of trkA and IGF-II expression in adrenal neuroblastomas (n = 25) also favored the nonoverlapping pattern of trkA and IGF-II expression (p < 0.05). Because IGF-II is believed to play a significant role in the tumorigenesis of neuroblastoma, the inverse relationship between trkA and IGF-II strongly suggests that a low level of trkA can be a feature of the pathogenetic mechanism of IGF-II expressing adrenal neuroblastomas.
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PMID:Insulin-like growth factor-II expression is down-regulated in TrkA-transfected SK-N-AS neuroblastoma cells. 1046 38

The insulin receptor-related receptor (IRR) is a member of the insulin receptor family. So far no ligand has yet been discovered for this receptor type (orphan receptor). IRR, insulin receptor (IR), and insulin-like growth factor-I receptor (IGF-I-R) are all tyrosine kinases. The cellular function of the IRR is not known. The expression of IRR mRNA is restricted to a few, e.g. neuronal tissues, and has also been found in neuroblastomas. Since tyrosine kinase receptors, including the IGF-I-R, may be involved in tumor genesis, we examined the expression of IRR mRNA and IGF-I-mRNA in 18 tumor cell lines using RT-PCR and the solution hybridization/RNAse protection assay. In particular, the mRNA levels of IRR and IGF-I-R were compared by semi-quantitative RT-PCR in seven neuroblastomas and 11 soft tissue sarcomas (STS), five of which were of neuronal origin. In all of the seven neuroblastoma cell lines and in five of the 11 STS cell lines, the IRR mRNA was detected. In addition, the IRR mRNA was expressed in rhabdomyosarcoma, in leiomyosarcoma, in one of the Ewing sarcoma and in the neurofibrosarcoma cell line. The last two tumor cell types are of neuronal origin. The levels of expression of IGF-I-R and IRR mRNA of the neuroblastoma cell lines were closely related (r = 0.82, P < 0.002). Furthermore, IRR mRNA was found only in cell lines that also expressed IGF-I-R mRNA. In conclusion, cell lines from pediatric tumors of neuronal origin express IRR mRNA simultaneously with a another tyrosine kinase receptor (IGF-I-R) mRNA. The tight coupling of their mRNA expression suggests a functional association of both receptors in the tumor cells.
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PMID:Correlation of type I insulin-like growth factor receptor (IGF-I-R) and insulin receptor-related receptor (IRR) messenger RNA levels in tumor cell lines from pediatric tumors of neuronal origin. 1053 6

Alternative splicing of the TrkB gene produces a full length tyrosine kinase receptor as well as two truncated isoforms that contain extracellular and transmembrane domains but lack the kinase domain and have unique C terminal tails. The function of the truncated TrkB isoforms is unclear and to gain insights into their function, we have isolated a protein from 15N neuroblastoma cells that specifically binds the TrkB.T1 isoform. Pulldown experiments using a GST fusion protein containing the TrkB.T1 intracellular domain identified a 61 kDa protein from radiolabeled 15N lysates. Coimmunoprecipitation experiments showed that the 61 kDa protein interacted with epitope-tagged TrkB.T1 overexpressed in 15N cells as well as with TrkB.T1 which was endogenously expressed. Peptide competition experiments revealed that the protein, designated TTIP (for Truncated TrkB Interacting Protein), showed specific binding to the TrkB.T1 tail. MALDI MS and MS/MS analysis has revealed that TTIP is a novel protein not yet listed in the current databases.
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PMID:TTIP is a novel protein that interacts with the truncated T1 TrkB neurotrophin receptor. 1116 51

Retinoic acid (RA) is a potent regulator of morphogenesis, growth and cell differentiation. Incubation with RA causes arrest of proliferation and neurite extension in SH-SY5Y cells, a neuroblastoma cell line of human origin. In these cells, RA regulates the expression of the beta-amyloid precursor protein. The retinoid increases the levels of intracellular and secreted forms of APP (amyloid precursor protein), APP-mRNA levels and the activity of the APP promoter in transient transfection studies. These responses require long periods of exposition to the ligand, thus suggesting a nondirect effect of the RA receptors on the APP gene. Also in these cells, RA induces the expression of TrkB, the tyrosine kinase receptor for brain-derived neurotrophic factor (BDNF), and 4 days of pretreatment with retinoic acid confers BDNF responsiveness to the APP promoter.
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PMID:Induction of tyrosine kinase receptor b by retinoic acid allows brain-derived neurotrophic factor-induced amyloid precursor protein gene expression in human SH-SY5Y neuroblastoma cells. 1292 7

The amyloid precursor protein (APP) is an ubiquitous receptor-like molecule involved in the pathogenesis of Alzheimer's disease (AD). APP and some of its C-terminal proteolytic fragments (CTFs) have been shown to be phosphorylated and to interact with cytosolic phosphotyrosine binding (PTB) domain containing proteins involved in cell signaling and vesicular transport. Among others, the interaction between tyrosine-phosphorylated CTFs and ShcA-Grb2 adaptors is highly enhanced in AD brain. Here we have identified in SH-SY5Y neuroblastoma cells an interaction between APP holoprotein and the adaptor Grb2. Upon activation of apoptotic cell death this interaction is rapidly degraded, APP is partially cleaved and the complex APP/Grb2 is replaced by a new complex between CTFs and ShcA that still involves Grb2. The formation of these complexes is regulated by beta-site APP-cleaving enzyme 1 and influences the phosphorylation of mitogen-activated protein kinase p44/42 extracellular signal-regulated kinase as well as the level of apoptotic death of the cells. These data suggest a dual role in cell signaling for APP and its CTFs in neuroblastoma cells, in a manner similar to that previously reported for other tyrosine kinase receptor, through a tightly regulated coupling with alternative intracellular adaptors to control the signaling of the cell.
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PMID:Apoptotic cell death influences the signaling activity of the amyloid precursor protein through ShcA and Grb2 adaptor proteins in neuroblastoma SH-SY5Y cells. 1534 20

Expression of neurotrophin receptors of the tyrosine kinase receptor (Trk) family is an important prognostic factor in solid tumors including neuroblastoma. High expression of TrkA (NTRK1) is associated with a favorable biology and outcome of neuroblastoma, whereas TrkB (NTRK2) is expressed on aggressive neuroblastomas with unfavorable outcome. To gain new insights into the global gene expression program resulting in these divergent biological phenotypes, we stably expressed either TrkA or TrkB in the human SH-SY5Y neuroblastoma cell line. Gene expression profiles were obtained from parental cells and transfectants activated by their ligands in a time course over 24 h using oligonucleotide microarrays. Basal activation of Trk receptors in the absence of exogenous ligand was sufficient to induce broad and divergent genetic changes. Global gene regulation following external ligand stimulation was surprisingly similar in SY5Y-TrkA and SY5Y-TrkB cells except for the differential expression of distinct novel target genes. Consistent with their divergent biological phenotype, SY5Y-TrkA cells were characterized by upregulation of proapoptotic genes and angiogenesis inhibitors, whereas SY5Y-TrkB cells demonstrated upregulation of genes involved in invasion or therapy resistance. We suggest that the transcriptional program of neuroblastoma cells is modulated by Trk-receptor expression and basal activation rather than by ligand-induced activation. Fine-tuning of the malignant phenotype may be achieved by additional ligand stimulation with subsequent activation of a few specific genes.
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PMID:Microarray analysis reveals differential gene expression patterns and regulation of single target genes contributing to the opposing phenotype of TrkA- and TrkB-expressing neuroblastomas. 1563 90


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