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 neural cell adhesion molecule NCAM plays an important role during neural development and in the adult brain. To study the intracellular trafficking of NCAM in neurons, two major isoforms, NCAM140 or NCAM180, were expressed in primary cortical neurons and in the rat B35 neuroblastoma cell line. NCAM was endocytosed and subsequently recycled to the plasma membrane, whereas only a minor fraction was degraded in lysosomes. In cortical neurons, endocytosis of NCAM was detected in the soma, neurites and growth cones in a developmentally regulated fashion. Furthermore, we found that NCAM is mono-ubiquitylated at the plasma membrane and endocytosis was significantly increased in cells overexpressing ubiquitin. Therefore, we propose that ubiquitylation represents an endocytosis signal for NCAM.
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PMID:NCAM is ubiquitylated, endocytosed and recycled in neurons. 1797 10

Hepatoblastoma is a malignant tumor that typically presents as a mass in the liver of a child less than 5 years of age. The diagnosis is usually established by means of a needle core biopsy before the treatment is commenced. The pathologic diagnosis of hepatoblastoma relies on the microscopic identification of typical morphologic features, but these may not be present in a needle core biopsy, and in this setting immunohistochemical staining has an important role in the exclusion of other childhood malignancies. We have studied 12 needle core biopsies from cases of hepatoblastoma, all of which had the diagnosis confirmed by subsequent resection of the tumor, to determine if these tumors show a diagnostic phenotype. The needle biopsies were immunostained with a standard panel of antibodies normally used in the characterization of childhood small round blue cell tumors, with the addition of antibodies directed against alpha-fetoprotein and alpha-1-antitrypsin. Our results indicate that the majority of hepatoblastomas expressed cytokeratins (10/12) and that alpha-1-antitrypsin and alpha-fetoprotein staining were positive in approximately half the cases (5/12 and 7/12, respectively). We also observed frequent expression of antigens normally expressed on other childhood tumors. A significant number of hepatoblastomas (8/12) expressed MIC-2 (CD99) an antigen normally associated with primitive neuroectodermal tumor, 4 cases showed positive staining with the neural-associated antigen NCAM (CD56), and 3 were positive with the neuroblastoma marker NB84. Occasional cases showed expression of the muscle marker desmin (2/12) and 2 cases stained with BCL2. Vimentin expression was seen in 1 case, and a single case also expressed the neural markers PGP9.5 and neurone-specific enolase. In all cases, the tumor cells were negative with CD45, WT1, and S-100. These findings indicate that the primitive cells in hepatoblastoma have a variable immunophenotype and can express antigens normally seen in other childhood malignancies. In the clinical setting of the differential diagnosis of childhood abdominal mass, hepatoblastoma shows no distinct immunohistochemical profile, and the diagnosis requires a combination of the clinical, imaging, and pathologic findings.
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PMID:Variable antigen expression in hepatoblastomas. 1822 29

Mammalian brains contain relatively high amounts of common and uncommon sialylated N-glycan structures. Sialic acid linkages were identified for voltage-gated potassium channels, Kv3.1, 3.3, 3.4, 1.1, 1.2 and 1.4, by evaluating their electrophoretic migration patterns in adult rat brain membranes digested with various glycosidases. Additionally, their electrophoretic migration patterns were compared with those of NCAM (neural cell adhesion molecule), transferrin and the Kv3.1 protein heterologously expressed in B35 neuroblastoma cells. Metabolic labelling of the carbohydrates combined with glycosidase digestion reactions were utilized to show that the N-glycan of recombinant Kv3.1 protein was capped with an oligo/poly-sialyl unit. All three brain Kv3 glycoproteins, like NCAM, were terminated with alpha2,3-linked sialyl residues, as well as atypical alpha2,8-linked sialyl residues. Additionally, at least one of their antennae was terminated with an oligo/poly-sialyl unit, similar to recombinant Kv3.1 and NCAM. In contrast, brain Kv1 glycoproteins consisted of sialyl residues with alpha2,8-linkage, as well as sialyl residues linked to internal carbohydrate residues of the carbohydrate chains of the N-glycans. This type of linkage was also supported for Kv3 glycoproteins. To date, such a sialyl linkage has only been identified in gangliosides, not N-linked glycoproteins. We conclude that all six Kv channels (voltage-gated K+ channels) contribute to the alpha2,8-linked sialylated N-glycan pool in mammalian brain and furthermore that their N-glycan structures contain branched sialyl residues. Identification of these novel and unique sialylated N-glycan structures implicate a connection between potassium channel activity and atypical sialylated N-glycans in modulating and fine-tuning the excitable properties of neurons in the nervous system.
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PMID:Atypical sialylated N-glycan structures are attached to neuronal voltage-gated potassium channels. 1893 45

Polysialylation of the neural cell adhesion molecule (NCAM PSA) is necessary for the consolidation processes of hippocampus-based learning. Previously, we have found inhibition of protein kinase C delta (PKCdelta) to be associated with increased polysialyltransferase (PST) activity, suggesting inhibitors of this kinase might ameliorate cognitive deficits. Using a rottlerin template, a drug previously considered an inhibitor of PKCdelta, we searched the Compounds Available for Purchase (CAP) database with the Accelrys((R)) Catalyst programme for structurally similar molecules and, using the available crystal structure of the phorbol-binding domain of PKCdelta, found that diferuloylmethane (curcumin) docked effectively into the phorbol site. Curcumin increased NCAM PSA expression in cultured neuro-2A neuroblastoma cells and this was inversely related to PKCdelta protein expression. Curcumin did not directly inhibit PKCdelta activity but formed a tight complex with the enzyme. With increasing doses of curcumin, the Tyr(131) residue of PKCdelta, which is known to direct its degradation, became progressively phosphorylated and this was associated with numerous Tyr(131)-phospho-PKCdelta fragments. Chronic administration of curcumin in vivo also increased the frequency of polysialylated cells in the dentate infragranular zone and significantly improved the acquisition and consolidation of a water maze spatial learning paradigm in both adult and aged cohorts of Wistar rats. These results further confirm the role of PKCdelta in regulating PST and NCAM PSA expression and provide evidence that drug modulation of this system enhances the process of memory consolidation.
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PMID:Curcumin-induced degradation of PKC delta is associated with enhanced dentate NCAM PSA expression and spatial learning in adult and aged Wistar rats. 1916 89

GAP-43 is the major neuronal substrate of protein kinase C (PKC). Its phosphorylation status dictates the severity of pathfinding errors by GAP-43 (+/-) growth cones in vivo, as well as its modulation of actin dynamics in vitro. These experiments show that stably overexpressing cDNAs mutant at its single PKC phosphorylation site at serine41 in retinoic acid treated SH-Sy5Y neuroblastoma cells regulates intrinsic and extrinsic behaviors of growing neurons. Intrinsically, only Wt and pseudophosphorylated GAP-43Ser41Asp precipitated with F-actin and potentiated F-actin - regulated filopodia formation. GAP-43Ser41Asp inhibited neurite outgrowth whereas only unphosphorylatable GAP-43Ser41Ala precipitated neurotubulin, potentiated neurotubulin accumulation in neurites and increased outgrowth. When PI3-kinase was inhibited GAP-43Ser41Asp-mediated filopodia formation was inhibited whereas GAP-43Ser41Ala-mediated neurite extension was potentiated. Extrinsically, only Wt and GAP-43Ser41Asp potentiated both homotypic adhesion and neurite outgrowth on NCAM-expressing monolayers and promoted NCAM stability. With respect to the underlying mechanism, more F-actin and NCAM colocalized with Wt and GAP-43Ser41Asp in detergent resistant membranes (DRMs) isolated from live cells and GAP-43Ser41Asp-mediated functions were insensitive to cholesterol depletion. In contrast, GAP-43Ser41Ala-mediated functions were sensitive to cholesterol depletion. Neither GAP-43Ser41Asp nor GAP-43Ser41Ala was able to protect against growth cone collapse mediated by PIP2 inhibitors. The results show that modification of GAP-43 at its PKC phosphorylation site directs its distribution to different membrane microdomains that have distinct roles in the regulation of intrinsic and extrinsic behaviors in growing neurons.
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PMID:Regulation of GAP-43 at serine 41 acts as a switch to modulate both intrinsic and extrinsic behaviors of growing neurons, via altered membrane distribution. 1924 69

We report a case of a 2 year-old girl who presented with three weeks' history of deterioration of walking, then became unable to walk and later she developed projectile vomiting. Neurological examination revealed bilateral papilledema, nystagmus, and truncal ataxia with intention tremor. Radiological studies showed an enhancing mass in the posterior fossa extending from the cerebellum to the roof of the fourth ventricle. The tumor was diagnosed as an embryonal tumor with abundant neuropil and true rosettes (ETANTR). The tumor cells in the neuroblastic component were diffusely positive for synaptophysin and CD56, with scattered positive cells for glial fibrillary acidic protein. The true rosettes were only positive for vimentin. Ki67 showed high index (over 90%) in the true rosettes, while the neuroblastic areas were up to 15%. Our patient developed recurrent disease 6 months after resection and chemotherapy. ETANTR is a very rare aggressive embryonal CNS tumor that combines features of neuroblastoma and ependymoblastoma. We review the thirteen cases reported in the literatures. This case represents the second report of an ETANTR arising in the cerebellum.
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PMID:Posterior fossa tumor in a 2 year-old girl. 1929 Oct 3

Glial cell line-derived neurotrophic factor (GDNF) transduces signal and promotes neurite outgrowths in diverse neurons through the interactions of GDNF family receptor alpha 1 (GFRalpha1) and other co-receptors including Ret receptor tyrosine kinase and NCAM. GFRalpha1 is alternatively spliced into two isoforms, GFRalpha1a and GFRalpha1b, with five amino acids difference. In this study, we found that both GFRalpha1a and GFRalpha1b were expressed in various human tissues. Interestingly, when stimulated with GDNF, GFRalpha1a but not GFRalpha1b promoted neurite outgrowth in neuroblastoma cells through the activations of ERK1/2, Rac1 and Cdc42. Remarkably, in cells co-expressing GFRalpha1a and GFRalpha1b, GDNF inhibited neurite outgrowths. The inhibitory activity of GFRalpha1b was dependent on RhoA and ROCK activation. Furthermore, GFRalpha1b but not GFRalpha1a activated Rho and various ROCK downstream effectors LIMK1/2, cofilin and MLC2. This study demonstrates the hitherto unrecognized roles of GFRalpha1 isoforms in the activation of distinct signaling pathways and in neurite outgrowths.
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PMID:GDNF-induced cell signaling and neurite outgrowths are differentially mediated by GFRalpha1 isoforms. 1946 53

Neuroblastoma tumors are derived from the neural crest and exhibit substantial phenotypic heterogeneity and various degrees of differentiation and maturation. The identification of new cell surface markers in neuroblastoma has relevance to disease classification and therapy. As a means to categorize neuroblastomas based on cell surface protein expression, we have obtained a comprehensive profile of the cell surface proteome of the MYCN nonamplified SH-SY5Y neuroblastoma cell line. Biotinylated cell surface proteins were captured using an avidin affinity column, fractionated by reversed-phase chromatography and subjected to in-depth analysis by LC-MS/MS. An extensive list of proteins was established and a subset of surface membrane proteins was assessed by immunohistochemistry in a set of neuroblastoma tissue microarrays. Among identified proteins tested, NCAM and CD147 exhibited increased expression in poorly differentiated tumors (p < 0.01 and <0.03, respectively). CD147 expression was previously associated with aggressive carcinomas but has not been described in neuroblastoma. This comprehensive neuroblastoma cell surface profile has identified novel potential markers for neuroblastoma classification and novel potential targets for therapy.
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PMID:Comprehensive profiling of the cell surface proteome of Sy5Y neuroblastoma cells yields a subset of proteins associated with tumor differentiation. 1950 85

To characterize natural killer (NK) cell subpopulations during activation, we analyzed the NK cell receptor repertoire and functionality of purified clinical scale CD56CD3 donor NK cells during stimulation with 1000 U/mL interleukin (IL)-2 for up to 14 days. In a phase I/II trial, we investigated the efficacy and feasibility of nonidentical NK cell infusion in patients with neuroblastoma after haploidentical stem cell transplantation. After IL-2 stimulation, large differences in the distribution of CD16 and CD16 subpopulations were found in 12 donors. Thereby, surface expression for all natural cytotoxicity receptors (NCRs) and NKG2D increased. In addition, killer cell immunoglobulin-like receptor (KIR) NK cells were overgrown by KIR proportion and the homing receptor CD62L was lost during stimulation. NK cell cytotoxicity against K562 and neuroblastoma cells increased and significantly higher cytokine secretion (eg, interferon-gamma, tumor necrosis factor-beta, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta) was observed after IL-2 stimulation compared with freshly isolated NK cells. However, NK cells of donors showing an initially enhanced cytotoxicity combined with NCR and CD69 expression, seemed to be exhausted and did not favor a stimulation period over 9 days. When IL-2-stimulated NK cells were given to transplant recipients, they induced a decrease of peripheral blood NK, in particular of CD56-NK cells. Our data indicate that IL-2 stimulation increases the expression of activating receptors and emphasizes mechanisms beside KIR/human leukocyte antigen. Furthermore, the results suggest that the expansion period of purified NK cells has to be individualized to optimize NK cell immunotherapy.
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PMID:IL-2-driven regulation of NK cell receptors with regard to the distribution of CD16+ and CD16- subpopulations and in vivo influence after haploidentical NK cell infusion. 2014 45

Neuroblastoma is one of the most common solid tumors occurring in childhood. Bone marrow evaluation is an important part of clinical staging in neuroblastoma patients. In view of the difficulty of detecting neuroblastoma cells with conventional bone marrow aspirate smears and biopsy (BMB) and specimens in cases in which metastasis is not prominent, we propose the use of immunohistochemistry (IHC) as a potential diagnostic tool. We examined 116 BMB and 115 bone marrow clot (BMC) specimens from 60 newly diagnosed neuroblastoma patients for tumor cells. Neuroendocrine IHC markers, such as CD56, chromogranin A, and synaptophysin were applied to diagnose neuroblastoma. Eighteen out of the 60 patients (25.4%) displayed BM metastasis, as observed with conventional hematoxylin and eosin staining. IHC staining of BMC sections was generally more sensitive than that of BMB sections for tumor cell detection. We detected tumors in 5 and 7 additional hematoxylin and eosin-negative BMB and BMC sections, respectively, using CD56. Overall, CD56 or a combination of CD56 and chromogranin A was effective in detecting neuroblastoma cells. IHC analysis of BMB and BMC sections is warranted as a routine component of the diagnostic work-up of neuroblastoma to overcome discrepancies between routine smears and IHC stains.
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PMID:Detection of bone marrow metastases of neuroblastoma with immunohistochemical staining of CD56, chromogranin A, and synaptophysin. 2021 6


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