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 amyloid beta/A4 protein precursor (APP), a large transmembrane protein, is expressed ubiquitously in many organisms, as well as in a variety of cultured cells. Studies of the synthesis and processing of APP have revealed several intricate metabolic pathways for this protein. One of these pathways involves the cleavage of APP in the middle of the beta/A4 domain and results in the secretion of the large amino-terminal portion of the protein. The biological function of this secreted form of APP has been the subject of intense investigation by several groups and various activities have been described for the different domains of APP studied. Our initial approach was to create a fibroblast cell line in which APP expression is dramatically reduced. These fibroblasts, called A-1, have a very slow growth rate. Addition of exogenous APP in the medium of A-1 cells restores their growth to the level of normal parent fibroblasts, demonstrating a growth factor-like activity for the secreted form of APP. Using APP fragments made in bacteria as well as synthetic peptides, we have been able to locate the active site of APP within a domain of 17 amino-acids (Ala319-Met335). This domain of APP can stimulate neurite extension of cultured neuroblastoma cells and it is proposed that APP mediates this effect through binding to a cell surface receptor, triggering intracellular transduction mechanisms. Thus, the secreted form of APP can function as a growth and/or differentiation factor and the site involved in these activities is within a 17-mer domain in the middle of the molecule. Our current lines of research seek to further characterize the mechanisms of APP function as well as its activity in vivo.
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PMID:Biologically active domain of the secreted form of the amyloid beta/A4 protein precursor. 823 74

The human fibroblast activation protein (FAP), defined by monoclonal antibody F19, is expressed in vivo in reactive stromal fibroblasts of epithelial cancers, subsets of bone and soft tissue sarcomas, and granulation tissue of healing wounds. FAP is generally absent from the stroma of benign epithelial tumors and normal adult tissues. In vitro FAP induction is observed in proliferating cultured fibroblasts and in melanocytes grown with fibroblast growth factor and phorbol ester. In the present study, we show that fibroblast and melanocyte FAP is a cell surface protein comprising noncovalently linked M(r) 95,000 (p95) and M(r) 105,000 (p105) subunits. In contrast, cultured sarcoma and melanoma cell lines express only p95 or are FAP negative. Immunoblot experiments show that p95, but not p105, carries the epitope defined by monoclonal antibody F19. Furthermore, peptide maps of purified p95 and p105 differ, suggesting that they may be distinct gene products. Loss of FAP or a change from p95/p105 to p95 expression accompanies the acquisition of growth factor independence and tumorigenicity in several in vitro test systems, including simian virus 40 transformation of normal fibroblasts, Ha-ras transformation of normal melanocytes, supertransformation of osteosarcoma cells, and enhanced N-MYC expression in variant neuroblastoma cells, whereas serum-starved normal fibroblasts continue to express p95/p105. Thus, fAP expression appears to be linked to the growth factor-dependent proliferative capacity of normal cells and is not merely a secondary event in proliferating cells; furthermore, FAP expression is inversely correlated with growth factor independence and tumorigenicity in transformed cell lines. This distribution pattern is consistent with a role for p95/p105 in mediating extrinsic, growth regulatory signals in normal cells, possibly as a heteromeric cell surface receptor. Such a physiological function may be obviated when oncogenes with cytoplasmic or nuclear sites of action are activated, reducing extrinsic growth factor dependence and permitting down-regulation of FAP in certain transformed cells.
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PMID:Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. 839 23

The processing of two homologous precursors, pro-neuropeptide Y (pro-NPY) and pro-pancreatic poly-peptide (pro-PP), was studied in four neuroendocrine cell lines after transfection: CA-77 medullary thyroid carcinoma cells, AtT-20 corticotrope pituitary cells, RIN2A-19 pancreatic endocrine cells, and NB1 neuroblastoma cells. Northern blot analysis indicated that the AtT-20 cells only expressed precursor convertase 3; in contrast, NB1 cells only expressed precursor convertase 2, whereas the RIN2A-19 and CA-77 cells expressed both enzymes. Despite these differences in expression pattern of precursor convertases the four cell lines were, surprisingly, indistinguishable in respect to their processing of pro-PP and pro-NPY. In all four cell lines, pro-NPY was almost completely converted to NPY, and, in all four cell lines, only around 50% of the PP precursor was converted to PP. The relatively poor processing efficiency of pro-PP was rather similar to the processing efficiency of the endogenously produced precursors in the respective cell lines, pro-calcitonin (CA-77), proopiomelanocortin (AtT-20), proinsulin (RIN2A-19), and pro-vasoactive intestinal polypeptide (NB1). At least in the CA-77 cells, NPY and PP were apparently sorted to the regulated secretory pathway, as upon stimulation with secretagogue the release of the transfected peptides increased in parallel with the endogenously expressed peptide, calcitonin gene-related peptide. Mutagenesis studies showed that on the N-terminal side of the di-basic processing site, the otherwise important difference in structure between PP and NPY, a proline for glutamine in position 34, was not responsible for the difference in processing efficiency. On the C-terminal side of the processing site, the efficient processing of pro-NPY could not be transferred to pro-PP by exchanging the whole C-terminal domains of the precursors. It is concluded that pro-NPY is processed more efficiently than pro-PP in all neuroendocrine cell lines tested independent on their expression of the two main precursor convertases and that mutagenesis data indicate that the structural element responsible for the efficient processing of pro-NPY is not located on the N-terminal side of the dibasic processing site.
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PMID:Processing of two homologous precursors, pro-neuropeptide Y and pro-pancreatic polypeptide, in transfected cell lines expressing different precursor convertases. 851 71

Expression of the RET proto-oncogene, a cell surface receptor for an as yet unknown ligand, is associated with tumors, tissues, and cell lines of neural crest origin. Accumulating evidence suggests that RET activity is involved in the process of neuronal differentiation. Moreover, induction of phenotypic differentiation of neuroblastoma cell lines is associated with the rapid accumulation of RET transcripts. To verify the role of RET in neuronal differentiation, we introduced into the human neuroblastoma cell line SK-N-BE four versions of the RET oncogene, activated by different mechanisms: RET/PTC1 and RET/PTC3, which are activated by rearrangement with heterologous genes; and two activated RET mutants, which carry the single amino acid substitution found associated to the inheritance of the multiple endocrine neoplasia type 2A (retMEN2A allele) and type2B (retMEN2B allele), respectively. We demonstrate that, after transfection with the RET oncogenes, SK-N-BE cells display a reduced growth rate and acquire a neurite-bearing phenotype accompanied by enhanced expression of the axonal growth-associated protein, GAP-43, and the high molecular weight neurofilament, NF200. These results indicate that, when activated, RET is able to cause growth inhibition and to promote neuronal differentiation of neuroblastoma cells.
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PMID:Expression of the RET oncogene induces differentiation of SK-N-BE neuroblastoma cells. 856 77

Ligation of the cell surface receptor Fas/APO-1 (CD95) by its specific ligand or by anti-Fas antibodies rapidly induces apoptosis in susceptible cells. To characterize the molecular events involved in Fas-induced apoptosis, we examined the contribution of two subgroups of the mitogen-activated protein (MAP) kinase family, the Jun kinases or stress-activated protein kinases (JNKs/SAPKs) and the extracellular signal-regulated kinases (ERKs), in a Fas-sensitive neuroblastoma cell line. Here we show that both JNK and ERK protein kinases were activated upon Fas crosslinking through a Ras-dependent mechanism. Interference with either the JNK or ERK pathway by ectopic expression of dominant-interfering mutant proteins blocked Fas-mediated apoptosis. ERK activation was transient and associated with induced expression of the Fas receptor. In contrast, JNK activation was sustained and correlated with the onset of apoptosis. These data indicate that the ERK and the JNK groups of MAP kinases cooperate in the induction of cell death by Fas. Inhibition of Fas killing by an interleukin 1beta-converting enzyme (ICE)-like protease inhibitor peptide did not modify Fas-induced JNK activation upon Fas ligation. In contrast, changes in Bcl-2 level due to expression of sense and antisense vectors influenced the sensitivity to Fas killing and Fas-induced JNK activation.
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PMID:Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway. 909 88

N-syndecan (syndecan-3) was previously isolated as a cell surface receptor for heparin-binding growth-associated molecule (HB-GAM) and suggested to mediate the neurite growth-promoting signal from cell matrix-bound HB-GAM to the cytoskeleton of neurites. However, it is unclear whether N-syndecan would possess independent signaling capacity in neurite growth or in related cell differentiation phenomena. In the present study, we have transfected N18 neuroblastoma cells with a rat N-syndecan cDNA and show that N-syndecan transfection clearly enhances HB-GAM-dependent neurite growth and that the transfected N-syndecan distributes to the growth cones and the filopodia of the neurites. The N-syndecan-dependent neurite outgrowth is inhibited by the tyrosine kinase inhibitors herbimycin A and PP1. Biochemical studies show that a kinase activity, together with its substrate(s), binds specifically to the cytosolic moiety of N-syndecan immobilized to an affinity column. Western blotting reveals both c-Src and Fyn in the active fractions. In addition, cortactin, tubulin, and a 30-kDa protein are identified in the kinase-active fractions that bind to the cytosolic moiety of N-syndecan. Ligation of N-syndecan in the transfected cells by HB-GAM increases phosphorylation of c-Src and cortactin. We suggest that N-syndecan binds a protein complex containing Src family tyrosine kinases and their substrates and that N-syndecan acts as a neurite outgrowth receptor via the Src kinase-cortactin pathway.
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PMID:Cortactin-Src kinase signaling pathway is involved in N-syndecan-dependent neurite outgrowth. 955 34

The bioactive phospholipid lysophosphatidic acid (LPA) causes growth cone collapse and neurite retraction in neuronal cells. These changes are brought about by the action of a cell surface receptor coupled to specific G proteins that control morphology and motility through the action of a group of small GTPases, the Rho family of proteins. Many studies have focused on actin reorganization modulated by Rho-GTPases, but almost no information has been obtained concerning microtubular network reorganization after LPA-induced neurite retraction. In the present study, we demonstrate an increase in site-specific Alzheimer's disease-like Tau phosphorylation during LPA-induced neurite retraction in differentiated SY-SH5Y human neuroblastoma cells. The phosphorylation state of Tau was inferred from its immunoreactivity with antibodies that recognize phosphorylation-sensitive epitopes. The effects of specific kinase inhibitors indicate that this phosphorylation is mediated by glycogen synthase kinase-3 (GSK-3). In support of this idea, we observed an increase of GSK-3 activity upon growth cone collapse. Our results are consistent with the hypothesis that activation of GSK-3 occurs in the Rho pathway and may represent an important link between microtubules and microfilaments dynamics during neuritogenesis and in pathological situations such as Alzheimer's disease.
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PMID:The neurite retraction induced by lysophosphatidic acid increases Alzheimer's disease-like Tau phosphorylation. 1060 Dec 62

1. Glial cell-derived neurothrophic factor (GDNF) interacts with a cell surface receptor, GFRalpha1, that is linked via a glycosyl-phosphatidylinositol (GPI) lipid to the cell membrane. The neurotrophic activities of GDNF are mediated by binding to GFRalpha1 and further interaction of the GDNF-GFRalpha1 complex with a coreceptor tyrosine kinase encoded by the c-Ret protooncogene. There is also evidence for the existence of cell signaling by GDNF and GFRalpha1 in the absence of Ret. 2. To further delineate the Ret-dependent and -independent functions of GDNF, cellular internalization of GDNF and GFRalpha1 was examined in cells lines and primary neurons. 3. Relative to other GPI-anchored receptors, efficient endocytosis (approximately 30-40% of total surface-bound ligand internalized after 2 min) of GNDF and GFRalpha1 was observed in neuroblastoma and transfected-fibroblast cell lines that lack Ret. Primary hippocampal neurons from transgenic mice that express a wild-type GFRalpha1 together with a mutant, tyrosine kinase-inactive Ret also internalized GDNF efficiently (approximately 20% of total surface-bound ligand internalized after 2 min). We also observed a ligand dependence for GFRalpha1 internalization in the cell lines that lack Ret. Furthermore, a comparison in the presence and absence of Ret indicates that this coreceptor tyrosine kinase slows internalization at early time points. 4. The data suggest different mechanisms of internalization for GDNF-GFRalpha1 in the absence and presence of the Ret coreceptor.
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PMID:Internalization of glial cell-derived neurotrophic factor receptor GFR alpha 1 in the absence of the ret tyrosine kinase coreceptor. 1270 83

Prions replicate in the host cell by the self-propagating refolding of the normal cell surface protein, PrP(C), into a beta-sheet-rich conformer, PrP(Sc). Exposure of cells to prion-infected material and subsequent endocytosis can sometimes result in the establishment of an infected culture. However, the relevant cell surface receptors have remained unknown. We have previously shown that cellular heparan sulfates (HS) are involved in the ongoing formation of scrapie prion protein (PrP(Sc)) in chronically infected cells. Here we studied the initial steps in the internalization of prions and in the infection of cells. Purified prion "rods" are arguably the purest prion preparation available. The only proteinaceous component of rods is PrP(Sc). Mouse neuroblastoma N2a, hypothalamus GT1-1, and Chinese hamster ovary cells efficiently bound both hamster and mouse prion rods (at 4 degrees C) and internalized them (at 37 degrees C). Treating cells with bacterial heparinase III or chlorate (a general inhibitor of sulfation) strongly reduced both binding and uptake of rods, whereas chondroitinase ABC was inactive. These results suggested that the cell surface receptor of prion rods involves sulfated HS chains. Sulfated glycans inhibited both binding and uptake of rods, probably by competing with the binding of rods to cellular HS. Treatments that prevented endocytosis of rods also prevented the de novo infection of GT1-1 cells when applied during their initial exposure to prions. These results indicate that HS are an essential part of the cellular receptor used both for prion uptake and for cell infection. Cellular HS thus play a dual role in prion propagation, both as a cofactor for PrP(Sc) synthesis and as a receptor for productive prion uptake.
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PMID:Heparan sulfate is a cellular receptor for purified infectious prions. 1566 47

As a neuroendocrine tumor, neuroblastoma expresses various gastrointestinal (GI) hormones, such as vasoactive intestinal peptide, gastrin-releasing peptide (GRP), neurotensin, and somatostatin, which exert diverse cellular functions in neuroblastoma. In particular, we have recently found that GRP and its cell surface receptor, GRP-R, are abundantly expressed in neuroblastomas. Moreover, more advanced-stage neuroblastomas demonstrated an increased level of GRP-R, suggesting an important role of GRP in aggressive tumor behavior. This review describes the role of several GI hormones commonly expressed in neuroblastoma and discusses in depth the mitogenic actions of GRP in neuroblastoma. In addition, the molecular mechanisms involved in the GRP-induced stimulation of neuroblastoma cell growth are discussed. Our study results demonstrate a role of GRP as an autocrine/paracrine growth factor and elucidate involvement of specific intracellular signaling, the phosphatidylinositol 3-kinase pathway, in the growth regulation of neuroblastoma.
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PMID:Role of gastrointestinal hormones in neuroblastoma. 1570 38


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