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 BM88 antigen is a neuron-specific molecule widely distributed in the mammalian nervous system. It is a 22-kDa, apparently not glycosylated, integral membrane protein, which appears early during brain development and remains at high levels in the mature animal. Here, we describe the cDNA cloning of the porcine BM88 antigen and present evidence that this protein is involved in neuroblastoma cell differentiation. The deduced protein is a novel molecule consisting of 140 amino acids and bears a putative transmembrane domain at the COOH-terminal region. The mRNA of this protein is expressed only in neural tissues, where it is restricted to neurons. Stably transfected Neuro-2a cells overexpressing the BM88 antigen exhibited a significant change in morphology, reflected by enhanced process outgrowth, and a slower rate of division. Moreover, in the presence of differentiation agents, such as sucrose and retinoic acid, an accelerated differentiation of the transfected Neuro-2a cells was observed. Especially in the presence of sucrose, the consequent overexpression of the BM88 antigen in the transfected cells resulted in their enhanced morphological differentiation accompanied by the induction of neurofilament protein expression. Our results suggest that the BM88 antigen plays a role in the differentiation of neuroblastoma cells.
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PMID:The BM88 antigen, a novel neuron-specific molecule, enhances the differentiation of mouse neuroblastoma cells. 777 80

Previous studies have shown that the BM88 antigen, a novel neuron-specific molecule, promotes the differentiation of mouse neuroblastoma (Neuro 2a) cells. In particular, stably transfected, with the BM88 cDNA, Neuro 2a cells overexpressing the BM88 antigen (Neuro2a-BM88 cells) are morphologically distinct from the nontransfected Neuro 2a cells; they exhibit enhanced process outgrowth and a slower rate of division. In this study we used Neuro2a and the morphologically differentiated Neuro 2a-BM88 cells to compare their responsiveness to growth factors. The growth factors we used were nerve growth factor (NGF), basic-fibroblast growth factor (b-FGF), and glial cell-line derived neurotrophic factor (GDNF). In addition, we used glial conditioned medium derived from either newborn mouse cerebral cortex (NBCC) or aged mouse cerebral hemispheres (MACH), as a source of normal glial factors. Because these cells express the cholinergic phenotype, we used choline acetyltransferase (ChAT) activity as a biochemical marker for comparison. A differential responsiveness to these factors was observed between Neuro 2a and Neuro 2a-BM88. The presence of NGF, 25 ng/ml, in the culture medium did not affect ChAT activity in either cell type. In contrast to NGF, in the presence of b-FGF, 5 ng/ml, the transfected cells, Neuro 2a-BM88, responded with a marked increase in ChAT activity. On the other hand, with GDNF, 1 ng/ml, only Neuro 2a cells showed an increase in ChAT activity. Finally, we found no response to the glial conditioned media, although these media contain several growth factors, including b-FGF. In conclusion, our findings show that overexpression of the neuron-specific antigen BM88 in neuroblastoma cells modifies their properties with respect to growth factor sensitivity, and, hence, the Neuro 2a and Neuro 2a-BM88 are suitable cell models to examine the role of growth factors in neuronal differentiation.
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PMID:Overexpression of the neuron-specific molecule BM88 in mouse neuroblastoma cells: altered responsiveness to growth factors. 945 16

Previous studies have shown that the BM88 antigen, a neuron-specific molecule, promotes the differentiation of mouse neuroblastoma cells [23] (Mamalaki A., Boutou E., Hurel C., Patsavoudi E., Tzartos S. and Matsas R. (1995) The BM88 antigen, a novel neuron-specific molecule, enhances the differentiation of mouse neuroblastoma cells. J. Biol. Chem. 270, 14201-14208). In particular, stably transfected with the BM88 cDNA, Neuro 2a cells over-expressing the BM88 antigen are morphologically distinct from their non-transfected counterparts; they exhibit enhanced process outgrowth and a slower rate of division. Moreover, they respond differentially to growth factors [10] (Gomez J., Boutou E., Hurel C., Mamalaki A., Kentroti S. , Vernadakis A. and Matsas R. (1998) Overexpression of the neuron-specific molecule BM88 in mouse neuroblastoma cells: Altered responsiveness to growth factors. J. Neurosci. Res. 51, 119-128). In order to further elucidate the role of the BM88 antigen in the differentiation of developing neurons we used the in vitro system of differentiating P19 cells which closely resembles early murine development in vivo. In this study, P19 cells were driven to the neuronal pathway with retinoic acid. We examined by immunofluorescence studies the expression of the BM88 antigen in these cells and we found that it correlates well with the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) which characterizes early differentiating post-mitotic neurons. In contrast, very few of the BM88 antigen-positive/PSA-NCAM-positive cells expressed neurofilament protein, a marker of more mature neurons. Our findings, in accordance with previously reported data, strongly suggest that the BM88 antigen is involved in the early stages of differentiation of neuronal cells.
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PMID:Early expression of the BM88 antigen during neuronal differentiation of P19 embryonal carcinoma cells. 1071 87

Porcine BM88 is a neuron-specific protein that enhances neuroblastoma cell differentiation in vitro and may be involved in neuronal differentiation in vivo. Here we report the identification, by Western blotting, of homologous proteins in human and mouse brain and the isolation of their respective cDNAs. Several human and mouse clones were identified in the EST database using porcine BM88 cDNA as a query. A human and a mouse EST clone were chosen for sequencing and were found both to predict a protein of 149 amino acids, with 79.9% reciprocal identity, and 76.4% and 70.7% identities to the porcine protein, respectively. This indicated that the clones corresponded to the human and mouse BM88 homologues. In vitro expression in a cell-free system as well as transient expression in COS7 cells yielded polypeptide products that were recognized by anti-BM88 antibodies and were identical in size to the native BM88 protein. Northern-blot analysis showed a wide distribution of the gene in human brain whereas immunohistochemistry on human brain sections demonstrated that the expression of BM88 is confined to neurons. The initial mapping assignment of human BM88 to chromosome 11p15.5, a region implicated in Beckwith-Wiedemann syndrome and tumorigenesis, was retrieved from the UniGene database maintained at the National Centre for Biotechnology Information (NCBI, Bethesda, MD, U.S.A.). We confirmed this localization by performing fluorescence in situ hybridization on BM88-positive cosmid clones isolated from a human genomic library. These results suggest that BM88 may be a candidate gene for genetic disorders associated with alterations at 11p15.5.
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PMID:Cloning, expression and localization of human BM88 shows that it maps to chromosome 11p15.5, a region implicated in Beckwith-Wiedemann syndrome and tumorigenesis. 1131 Nov 34

Progression of progenitor cells towards neuronal differentiation is tightly linked with cell cycle control and the switch from proliferative to neuron-generating divisions. We have previously shown that the neuronal protein BM88 drives neuroblastoma cells towards exit from the cell cycle and differentiation into a neuronal phenotype in vitro. Here, we explored the role of BM88 during neuronal birth, cell cycle exit and the initiation of differentiation in vivo. By double- and triple-labelling with the S-phase marker BrdU or the late G2 and M-phase marker cyclin B1, antibodies to BM88 and markers of the neuronal or glial cell lineages, we demonstrate that in the rodent forebrain, BM88 is expressed in multipotential progenitor cells before terminal mitosis and in their neuronal progeny during the neurogenic interval, as well as in the adult. Further, we defined at E16 a cohort of proliferative progenitors that exit S phase in synchrony, and by following their fate for 24 h we show that BM88 is associated with the dynamics of neuron-generating divisions. Expression of BM88 was also evident in cycling cortical radial glial cells, which constitute the main neurogenic population in the cerebral cortex. In agreement, BM88 expression was markedly reduced and restricted to a smaller percentage of cells in the cerebral cortex of the Small eye mutant mice, which lack functional Pax6 and exhibit severe neurogenesis defects. Our data show an interesting correlation between BM88 expression and the progression of progenitor cells towards neuronal differentiation during the neurogenic interval.
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PMID:BM88 is an early marker of proliferating precursor cells that will differentiate into the neuronal lineage. 1554 96

Control of cell cycle progression/exit and differentiation of neuronal precursors is of paramount importance during brain development. BM88 is a neuronal protein associated with terminal neuron-generating divisions in vivo and is implicated in mechanisms underlying neuronal differentiation. Here we have used mouse neuroblastoma Neuro 2a cells as an in vitro model of neuronal differentiation to dissect the functional properties of BM88 by implementing gain- and loss-of-function approaches. We demonstrate that stably transfected cells overexpressing BM88 acquire a neuronal phenotype in the absence of external stimuli, as judged by enhanced expression of neuronal markers and neurite outgrowth-inducing signaling molecules. In addition, cell cycle measurements involving cell growth assays, BrdUrd incorporation, and fluorescence-activated cell sorting analysis revealed that the BM88-transfected cells have a prolonged G(1) phase, most probably corresponding to cell cycle exit at the G(0) restriction point, as compared with controls. BM88 overexpression also results in increased levels of the cell cycle regulatory protein p53, and accumulation of the hypophosphorylated form of the retinoblastoma protein leading to cell cycle arrest, with concomitant decreased levels and, in many cells, cytoplasmic localization of cyclin D1. Conversely, BM88 gene silencing using RNA interference experiments resulted in acceleration of cell proliferation accompanied by impairment of retinoic acid-induced neuronal differentiation of Neuro 2a cells. Taken together, our results suggest that BM88 plays an essential role in regulating cell cycle exit and differentiation of Neuro 2a cells toward a neuronal phenotype and further support its involvement in the proliferation/differentiation transition of neural stem/progenitor cells during embryonic development.
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PMID:BM88 is a dual function molecule inducing cell cycle exit and neuronal differentiation of neuroblastoma cells via cyclin D1 down-regulation and retinoblastoma protein hypophosphorylation. 1689 93

In neurogenesis, little is known about signal transduction pathways upstream of gene expression however, mounting evidence suggests that calcium release from internal stores plays a critical role. We have previously demonstrated that BM88 is a neuronal lineage-specific regulator of cell cycle exit and differentiation; we now report a link between BM88 and calcium signaling. Calcium imaging experiments revealed that P2Y-induced calcium mobilization is diminished in mouse neuroblastoma Neuro 2a cells stably transfected with BM88 (N2A-BM88 cells) as compared with N2A cells or N2A cells differentiated with retinoic acid. This effect is not restricted to N2A cells but is also observed in HeLa cells that are transiently transfected with BM88, indicating that cells of both neural and non-neural origin respond similarly. Further, activation of P2Y1 but not purinergic P2X receptors induces proliferation of N2A and to a lesser extent of N2A-BM88 cells. Conversely, knockdown of BM88 facilitates N2A cell proliferation both under stimulating and non-stimulating conditions. Importantly, N2A-BM88 cells are less susceptible to apoptosis triggered by C2-ceramide and exhibit reduced C2-ceramide-induced intracellular calcium release. Higher calcium uptake from mitochondria and/or lower calcium levels inside the endoplasmic reticulum may explain the reduced calcium mobilization in response to BM88. Overall, our data reveal a novel signaling mechanism by which BM88 interferes with calcium release from inositol 1,4,5-trisphosphate-sensitive stores and exerts anti-proliferative and anti-apoptotic functions.
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PMID:BM88/Cend1 regulates stimuli-induced intracellular calcium mobilization. 1906 3

BM88/Cend1 is a neuronal-lineage specific modulator with a pivotal role in coordination of cell cycle exit and differentiation of neuronal precursors. In the current study we identified the signal transduction scaffolding protein Ran-binding protein M (RanBPM) as a BM88/Cend1 binding partner and showed that BM88/Cend1, RanBPM and the dual specificity tyrosine-phosphorylation regulated kinase 1B (Dyrk1B) are expressed in mouse brain as well as in cultured embryonic cortical neurons while RanBPM can form complexes with either of the two other proteins. To elucidate a potential mechanism involving BM88/Cend1, RanBPM and Dyrk1B in cell cycle progression/exit, we transiently co-expressed these proteins in mouse neuroblastoma Neuro 2a cells. We found that the BM88/Cend1-dependent or Dyrk1B-dependent down-regulation of cyclin D1 is reversed following their functional interaction with RanBPM. More specifically, functional interaction of RanBPM with either BM88/Cend1 or Dyrk1B stabilizes cyclin D1 in the nucleus and promotes 5-bromo-2'-deoxyuridine (BrdU) incorporation as a measure of enhanced cell proliferation. However, the RanBPM-dependent Dyrk1B cytosolic retention and degradation is reverted in the presence of Cend1 resulting in cyclin D1 destabilization. Co-expression of RanBPM with either BM88/Cend1 or Dyrk1B also had a negative effect on Neuro 2a cell differentiation. Our results suggest that functional interactions between BM88/Cend1, RanBPM and Dyrk1B affect the balance between cellular proliferation and differentiation in Neuro 2a cells and indicate that a potentially similar mechanism may influence cell cycle progression/exit and differentiation of neuronal precursors.
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PMID:Functional Interactions between BM88/Cend1, Ran-binding protein M and Dyrk1B kinase affect cyclin D1 levels and cell cycle progression/exit in mouse neuroblastoma cells. 2431 6