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)

We have used monoclonal antibodies to statin (S-44) and a cyclin-like protein (S-132) to examine the distribution of these two antigens in proliferating and in nonproliferating populations of cells. We have found that this cyclin-like protein is present in proliferating fibroblasts, whereas statin is absent from these same cell populations; in contrast, in senescent populations of fibroblasts the cyclin-like antigen disappears and statin labeling of nuclei appears. During myogenesis in rat muscle cell cultures, S-132 labeling is present in proliferating myoblasts and disappears after cells fuse and differentiate as multinucleated myotubes. In contrast, statin is absent from proliferating myoblasts, but appears when these cells become postmitotic and begin to differentiate. Similar results were seen during chick myogenesis. We have also found similar results during serum-starvation-induced differentiation in neuroblastoma cells. These results indicate that the cyclin-like protein disappears and statin appears upon commitment to differentiation in vitro, and the presence or the absence of these proteins appears to provide cellular markers for the transition from the proliferative to the nonproliferative state during differentiation.
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PMID:The disappearance of a cyclin-like protein and the appearance of statin is correlated with the onset of differentiation during myogenesis in vitro. 289 89

We are employing recent advances in the understanding of the cell cycle to study the inverse relationship between proliferation and neuronal differentiation. Nerve growth factor and aphidicolin, an inhibitor of DNA polymerases, synergistically induce neuronal differentiation of SH-SY5Y neuroblastoma cells and the expression of p21WAF1, an inhibitor of cyclin-dependent kinases. The differentiated cells continue to express p21WAF1, even after removal of aphidicolin from the culture medium. The p21WAF1 protein coimmunoprecipitates with cyclin E and inhibits cyclin E-associated protein kinase activity. Each of three antisense oligonucleotides complementary to p21WAF1 mRNA partially blocks expression of p21WAF1 and promotes programmed cell death. These data indicate that p21WAF1 expression is required for survival of these differentiating neuroblastoma cells. Thus, the problem of neuronal differentiation can now be understood in the context of negative regulators of the cell cycle.
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PMID:The cyclin-dependent kinase inhibitor p21 (WAF1) is required for survival of differentiating neuroblastoma cells. 865 6

The effect of the cyclin-dependent (CDK) inhibitors olomoucine and roscovitine on cell kinetics was studied. To this end, nonsmall cell lung cancer (NSCLC) cell line MR65 and neuroblastoma cell line CHP-212 were pulse labeled with bromodeoxyuridine (BrdUrd) and chased in culture medium, to which various concentrations of olomoucine or roscovitine were added. A dose-dependent inhibition of the G1/S-phase and G2/ M-/G1 transitions was observed. Furthermore, S-phase progression was also inhibited in a dose-dependent manner. Similarly, roscovitine, another CDK inhibitor with a 10-fold higher efficiency for both CDK1 and CDK2 as compared to olomoucine, showed the same effects at a 10-fold lower concentration. At the highest tested doses both olomoucine (200 microM) and roscovitine (40 microM) induced a complete cell cycle block in both cell lines, paralleled by the appearance of apoptotic figures. In these cultures a decrease in CDK1 protein level was found as shown by Western blotting. Bivariate CDK1/DNA analysis confirmed these observations and showed that a subpopulation of cells with characteristics of apoptosis became CDK1 negative. The presented data suggest that cyclins and CDKs are involved at an important nodal point shared by pathways regulating cellular proliferation and apoptosis.
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PMID:The effect of the cyclin-dependent kinase inhibitor olomoucine on cell cycle kinetics. 934 80

The p21 protein inhibits the activity of cyclin-Cdk complexes and suppresses cell cycle progression. Wild type p53 can induce p21, but mutated p53 cannot. Previous studies have demonstrated that mutation of p53 is absent in neuroblastoma (NB). These reports prompted us to examine whether p53 induced p21 in NB. We examined the expression of p21 and p53 mRNA in eight NB, two Ewing's sarcoma (ES) and two primitive neuroectodermal tumor (PNET) cell lines by Northern blot analysis, and sequenced p53 cDNA of these cells. Although p53 mRNA was detected in all analyzed cell lines by Northern blot analysis, p21 mRNA was detected in six NB but not in two NB, two ES and two PNET cell lines. We detected the point mutation of p53 at codon 273 (CGT to TGT) in one NB and two ES cell lines. The non-transforming substitution at codon 72 (CCC to CGC) was detected in all analyzed cell lines. One PNET cell line had a large deletion of p53 cDNA. These results showed that p21 mRNA was usually expressed in NB but not in ES and PNET. This may suggest that the down stream of the p53 signal transduction pathway in NB is different from that of the closely related tumors of ES and PNET.
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PMID:p21 (WAF1/Cip1/Sdi1/Pic1) mRNA is expressed in neuroblastoma cell lines but not in Ewing's sarcoma and primitive neuroectodermal tumor cell lines. 936 58

There is increasing evidence that apoptosis in postmitotic neurons is associated with a frustrated attempt to reenter the mitotic cycle. Okadaic acid, a specific protein phosphatase inhibitor, is currently used in models of Alzheimer's research to increase the degree of phosphorylation of various proteins, such as the microtubule-associated protein tau. Okadaic acid induces programmed cell death in the human neuroblastoma cell lines TR14 and NT2-N, as evidenced by fragmentation of DNA and attenuation of this process by protein synthesis inhibitors. In differentiated TR14 cells, okadaic acid increases the fraction of cells in the S phase, induces the appearance of cyclin B1 and cyclin D1 markers of the cell cycle, and triggers a time-dependent increase in DNA fragmentation after release of a thymidine block. Fully differentiated NT2-N cells are forced to enter the mitotic cycle as shown by DNA staining. Chromatin condensation and chromosome formation are initiated, but the cells fail to complete their mitotic cycle. These data suggest that okadaic acid forces differentiated neuronal cells into the mitotic cycle. This pattern of cyclin up-regulation and cell cycle shift is compared with apoptosis induced by neurotrophic factor deprivation in differentiated rat pheochromocytoma PC12 cells.
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PMID:Okadaic acid-induced apoptosis in neuronal cells: evidence for an abortive mitotic attempt. 948 33

Phosphorylation at certain proline-directed sites on the microtubule-associated protein 1B (MAP1B) is a characteristic feature of mitotic neuronal precursor cells and developing neurons and is particularly abundant within growing axons. This mode of MAP1B phosphorylation disappears from mature neurons, except in those neurons that have a high regenerative potential, and is aberrantly up-regulated in degenerating neurons within the brains of Alzheimer's disease patients. Here, we report that this type of MAP1B phosphorylation is practically abolished in proliferating neuroblastoma cells that are treated with chemical inhibitors of cyclin-dependent kinases. In contrast, these drugs have no significant effect on MAP1B phosphorylation in either differentiated neuroblastoma cells or cerebellar granule neurons. Interestingly, lithium, which is a potent inhibitor of glycogen synthase kinase 3, suppresses this mode of MAP1B phosphorylation in differentiated neuroblastoma cells and cerebellar granule neurons. This is consistent with a major role of cyclin-dependent kinases in catalyzing this type of MAP1B phosphorylation in proliferating neural cells, whereas glycogen synthase kinase 3 would be largely responsible for this mode of MAP1B phosphorylation in postmitotic neurons that are extending axons. Both cyclin-dependent kinases and glycogen synthase kinase 3 might contribute to the aberrant MAP1B phosphorylation observed in Alzheimer's disease.
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PMID:Implication of cyclin-dependent kinases and glycogen synthase kinase 3 in the phosphorylation of microtubule-associated protein 1B in developing neuronal cells. 958 89

Retinoic acid (RA) treatment of SMS-KCNR neuroblastoma (NB) cells leads to G1 growth arrest and neuronal differentiation. To investigate the molecular mechanisms by which RA alters cell growth, we analysed the expression and activity of components of the cell cycle machinery after culture in RA. Within 2 days of RA treatment and prior to the arrest of NB cells in the G1 phase of the cell cycle, there is a complete downregulation of G1 cyclin/Cdk activities. Protein levels for the G1 cyclin/Cdks were essentially unchanged during this time although there was a decrease in the steady-state levels of p67N-Myc and hyperphosphorylated Rb proteins. The Cdk inhibitors, p21Cip1 and p27Kip1 were constitutively expressed in KCNR while p15INK4B and p16INK4A were not detected. RA induced an increase in the expression of p27Kip1 but not p21Cip1. Furthermore, coincident with the decrease in kinase activity there was an increase in G1 cyclin/Cdk bound p27Kip1. These results indicate that changes in the level of p27Kip1 and its binding to G1 cyclin/Cdks may play a key role in RA induced growth arrest of NB cells.
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PMID:p27Kip1: a key mediator of retinoic acid induced growth arrest in the SMS-KCNR human neuroblastoma cell line. 968 34

The thyroid hormone (triiodothyronine, T3) is essential for normal brain maturation. To determine the mechanisms by which T3 controls neuronal proliferation and differentiation, we have analyzed the effect of this hormone on the expression and activity of cell cycle-regulating molecules in neuroblastoma N2a-beta cells that overexpress the beta1 isoform of the T3 receptor. Our results show that incubation of N2a-beta cells with T3 leads to a rapid down-regulation of the c-myc gene and to a decrease of cyclin D1 levels. T3 also causes a strong and sustained increase of the levels of the cyclin kinase inhibitor p27(Kip1). This increase is secondary, to the augmented levels of p27(Kip1) transcripts as well as to stabilization of the p27(Kip1) protein. The increased levels of p27(Kip1) lead to a significant increase in the amount of p27(Kip1) associated with cyclin-dependent kinase 2 (CDK2), and to a marked inhibition of the kinase activity of the cyclin.CDK2 complexes. As a consequence, the retinoblastoma protein (pRb) and the retinoblastoma protein-related protein p130 are hypophosphorylated in T3-treated N2a-beta cells. This study shows for the first time that T3-mediated growth arrest and neuronal differentiation are associated with an increase in the levels of a cyclin kinase inhibitor, which does not allow the inactivation of retinoblastoma proteins required for progression through the restriction point in the cell cycle.
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PMID:The cyclin-dependent kinase inhibitor p27(Kip1) is involved in thyroid hormone-mediated neuronal differentiation. 998 48

Neuroblastoma cells are used as a model system to study neuronal differentiation. Here we describe the induction of morphological differentiation of mouse neuroblastoma Neuro 2a (N2a) cells by treatments with either chemical inhibitors of cyclin-dependent kinases or lithium, which inhibits glycogen synthase kinase-3. Cyclin-dependent kinase inhibitors cause a rapid cell cycle block as well as the extension of multiple neurites per cell. These multipolar differentiated cells then undergo a massive death. However, lithium promotes a delayed mitotic arrest and the extension of one or two long neurites per cell. This differentiation is maximal after 48 hours of lithium treatment and the differentiated cells remain viable for long periods of time. Neuronal differentiation in lithium-treated cells is preceded by the accumulation of beta-catenin, a protein which is efficiently proteolyzed when it is phosphorylated by glycogen synthase kinase-3. Both neuronal differentiation and beta-catenin accumulation are observed in lithium-treated cells either in the absence or in the presence of supraphysiological concentrations of inositol. The results are consistent with the hypothesis that inhibition of glycogen synthase kinase-3 by lithium triggers the differentiation of neuroblastoma N2a cells.
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PMID:Lithium induces morphological differentiation of mouse neuroblastoma cells. 1039 4

Although viral gene expression occurs in the peripheral nervous system during acute infection, bovine herpesvirus 1 (BHV-1) gene expression is extinguished, many neurons survive, and latency ensues. The only abundant viral transcript expressed during latency is the latency-related (LR) RNA, which is alternatively spliced in trigeminal ganglia during acute infection (L. Devireddy and C. Jones, J. Virol. 72:7294-7301, 1998). A subset of neurons express a protein encoded by the LR gene and the LR protein (LRP) is associated with cyclin-dependent kinase 2 (Cdk2)/cyclin complexes during productive infection (Y. Jiang, A. Hossain, M. T. Winkler, T. Holt, A. Doster, and C. Jones, J. Virol. 72:8133-8142, 1998). LR gene products inhibit cell cycle progression, perhaps as a result of LRP interacting with Cdk2/cyclin complexes. During acute infection, expression of cyclin A occurs in trigeminal ganglionic neurons (L. M. Schang, A. Hossain, and C. Jones, J. Virol. 70:3807-3814, 1996). Inappropriate expression of G(1)- and S-phase cyclins can initiate programmed cell death (PCD), apoptosis, in neurons, suggesting that LR gene products inhibit PCD. To test this hypothesis, we modified an assay to measure PCD frequency in transiently transfected cells. C(6)-ceramide, fumonisin B(1) (FB(1)), or etoposide was used to initiate PCD following transfection of cells with plasmids expressing LR gene products and the beta-galactosidase gene. Transfected cells that survived were quantified by counting beta-galactosidase-positive cells. Plasmids that expressed LR gene products promoted survival of monkey kidney (CV-1), human lung (IMR-90), or mouse neuroblastoma (neuro-2A) cells after induction of PCD. Plasmids with termination codons at the beginning of LR open reading frames or deletion of sequences that mediate splicing of LR RNA did not promote cell survival following PCD induction. We hypothesize that LR gene products play a role in promoting survival of postmitotic neurons during acute infection or reactivation.
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PMID:The latency-related gene of bovine herpesvirus 1 inhibits programmed cell death. 1055 83


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