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)

1. Investigations have demonstrated that the gene encoding thymosin beta 10 (a 43-amino acid member of a family of related proteins originally described in the rat immune system) is a target for morphogenic retinoids in both human and rat neuroblastoma cells. 2. Structure-activity studies revealed that the stimulatory actions of retinoids upon the thymosin beta 10 gene reflect the differing affinities of retinoid analogues for a retinoic acid receptor. 3. To examine further the possibility that the trophic actions of retinoic acid upon expression of the thymosin beta 10 gene involved retinoid receptors, neuroblastoma cells were transiently transfected with an expression vector encoding the nuclear retinoic acid receptor (alpha) protein. 4. Northern blot and slot-blot analyses revealed that neuronal cells overexpressing RAR alpha-mRNA exhibited an enhanced sensitivity to exogenous and endogenous retinoic acid in terms of thymosin beta 10 mRNA. Although the RAR-alpha gene was expressed (at low levels) a priori in these neuroblastoma cells, retinoic acid (2 x 10(-7) M for 3 days) slightly stimulated RAR-alpha-mRNA accumulation. 5. Collectively, these findings indicate the retinoic acid receptor (alpha) is regulated by retinoid acid and that the developmentally regulated, retinoid-responsive thymosin beta 10 gene is a target for this nuclear transcription factor in cells derived from the neural crest.
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PMID:Retinoids and a retinoic acid receptor differentially modulate thymosin beta 10 gene expression in transfected neuroblastoma cells. 131 16

Using monoclonal antibodies against the RAR-alpha and RAR-beta retinoic receptors, we demonstrated that these receptors were present together in C6 glioma cells as two isoforms of 50 and 55 kDa. For RAR-beta, the 50 kDa isoform predominated (60 to 80% of the total of the two isoforms). After a treatment for 48 h with retinoic acid 10 microM, the 55 kDa form was enhanced, while no effect was observed either on RAR-alpha isoforms from C6 cells and on both RAR-alpha and RAR-beta forms from neuroblastoma SKN SH SY5Y used as a control. Using purified neuronal and glial rat brain nuclei, we showed that the 55 kDa isoform from RAR-beta predominated in glial cells. These results suggest that retinoic acid treatment of C6 cells led to a partial differentiation, the enhancement of the heavy form of RAR-beta being a marker of this phenomenon.
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PMID:Study of retinoic acid effect upon retinoic acid receptors beta (RAR-beta) in C6 cultured glioma cells. 758 Oct 5

All-trans-retinoic acid (RA) and retinoids induce synthesis of tissue-type plasminogen activator (t-PA) in endothelial and neuroblastoma cells in vitro and in rats in vivo. In HT1080 fibrosarcoma cells, induction of t-PA-related antigen secretion and t-PA mRNA steady state levels by RA were found to depend on de novo protein and mRNA synthesis. Fragments derived from the 5'-flanking region of the t-PA gene (+197 to -9578 base pairs (bp)) were linked to the chloramphenicol acetyltransferase gene. Transfection studies demonstrated that the region spanning bp -7145 to -9578 mediated induction by RA. A functional retinoic acid response element (RARE), consisting of a direct repeat of the GGGTCA motif spaced by 5 nucleotides (t-PA/DR5), was localized at -7.3 kilobases. The t-PA/DR5 element interacted with the heterodimer composed of retinoic acid receptor alpha and retinoid X receptor alpha in vitro, whereas its mutation abolished induction by RA in transient expression. In human EA.hy926 hybrid endothelial and in SK-N-SH neuroblastoma cells, the activity of t-PA/DR5 was found to be independent of the intervening sequence (-632 to -7144 bp) and of its distance from the transcription initiation site. Staurosporine, an inhibitor of protein kinase activity, inhibited induction by RA, suggesting that it required protein phosphorylation.
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PMID:Retinoic acid induction of human tissue-type plasminogen activator gene expression via a direct repeat element (DR5) located at -7 kilobases. 770 55

Human neuroblastoma (NB) cell lines treated with all-trans retinoic acid (RA) differentiate in culture, forming neurites and exhibiting growth arrest. We treated 5 human NB cell lines with RA, and observed a 2-5 fold induction of retinoic acid receptor alpha (RAR alpha) mRNA expression in 4 of the 5 cell lines, as an early cellular response. Induction of RAR alpha expression was specific for RA among several differentiating agents tested. RAR alpha mRNA expression in 13 primary neuroblastoma tumor samples was 3 fold higher in localised compared with advanced tumors (p < 0.05). RAR alpha expression may be necessary for the effects of RA on NB cells in vitro and reduced expression of this gene in vivo may contribute to the process of NB tumorigenesis.
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PMID:Regulation of retinoic acid receptor alpha expression in human neuroblastoma cell lines and tumor tissue. 801 44

We investigated the potential for 9-cis-retinoic acid in the differentiation therapy of neuroblastoma using an N-type neuroblastoma cell line, SH SY 5Y, as an experimental model. In these cells, 9-cis-retinoic acid is more effective than other isomers at inducing the expression of RAR-beta. An RAR-alpha-specific antagonist inhibited the induction of RAR-beta in response to all-trans-but not to 9-cis-retinoic acid. This indicates that the mechanism of gene induction by 9-cis-retinoic acid differs markedly from all-trans-retinoic acid. 9-cis-retinoic acid is also better than all-trans at producing sustained morphological differentiation and inhibition of proliferation of SH SY 5Y cells. Although N-type neuroblastoma cells are not thought to undergo apoptosis in response to all-trans-retinoic acid, we observed a significant degree of apoptosis in SH SY 5Y cells treated with 9-cis-retinoic acid for 5 days and then cultured in the absence of retinoid, an effect not observed in cells treated with the all-trans isomer. These results suggest that 9-cis- and all-trans-retinoic acid have distinct biological properties and that 9-cis retinoic acid may be clinically effective in neuroblastoma by inducing both differentiation and apoptosis under an appropriate treatment regimen.
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PMID:Retinoids in neuroblastoma therapy: distinct biological properties of 9-cis- and all-trans-retinoic acid. 951 56

Retinoids modulate several cell functions and especially inhibit the growth of tumor cells. Their biological activity is mediated by retinoic acid receptors (RARs), of which three subtypes (alpha, beta, gamma) have been identified. In human neuroblastoma (NB) reduced endogenous RAR-gamma expression was suggested to diminish the sensitivity for retinoids, to promote proliferation, and to contribute to the malignant phenotype. To correlate receptor selectivity with in vitro activity, we analysed the effect of six synthetic retinoids with selectivity for human RAR-alpha/beta/gamma on the human LAN-5 NB cell line and compared it with the natural compound all-trans-retinoic acid (ATRA). Apoptosis was determined by flow-cytometry using terminal-deoxynucleotidyl transferase to end-label DNA fragments in situ in apoptotic cells. The antagonist for RAR-beta/gamma CD2665 as well as the selective agonists for RAR-alpha CD336 and RAR-beta CD2019 were less effective in growth inhibition than ATRA. In contrast, the synthetic RAR-gamma selective agonists CD437 and CD2325 induced a concentration- and time-dependent antiproliferative effect, which was similar or even more pronounced than ATRA. In contrast to ATRA, the adition of CD437 and CD2325 did not induce morphological changes typical of NB cell maturation but resulted in morphological features consistent with the occurrence of programmed cell death. Flow-cytometric analysis showed that in contrast to ATRA the addition of CD 437 and CD 2325 results in progressive time-dependent increase of apoptotic cells (25.9% and 57.7% after 72 hours). In conclusion, our study demonstrates RAR-gamma selectively binding retinoids dramatically suppress NB cell growth, primarily by inducing programmed cell death rather than by cell differentiation. Since advanced or disseminated NB tumors endogenously express low levels of RAR-gamma and lack of apoptosis is involved in tumor progression, RAR-gamma selectively binding retinoids may be more appropriate retinoids for clinical trials in NB.
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PMID:Antiproliferative activity and apoptosis induced by retinoic acid receptor-gamma selectively binding retinoids in neuroblastoma. 967 4

The promyelocytic leukemia (PML) protein, whose fusion with retinoic acid receptor alpha is responsible for the tumorigenesis of acute promyelocytic leukemia, acts as a tumor suppressor in various types of human cancers. We analyzed the expression patterns of PML, in both primary neuroblastic tumors ( n=20) and two human neuroblastoma (NB) cell lines, SMS-KCNR (KCNR) and SH-SY5Y (SY5Y). The expression of PML, revealed as speckled or microgranular staining in the nuclei, was positively correlated with the differentiation status of NB cells in vivo, and was upregulated during the differentiation of KCNR and SY5Y cells following retinoic acid treatment. Screening of PML expression in human brain and sympathetic ganglia showed restricted expression of PML in mature neurons and glial cells, a result that was consistent with that in differentiated NB tumors. All these findings strongly suggest that increased PML expression is associated with growth inhibition and differentiation of human NB cells, and that it is of critical significance in the biology of NBs and in human nervous system development.
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PMID:Expression of promyelocytic leukemia protein increases during the differentiation of human neuroblastoma cells. 1264 19

To seek a novel therapeutic approach to neuroblastoma (NBL), we used three NBL cell lines (SK-N-DZ, NH12, and SK-N-SH) to examine the underlining molecular mechanisms of cellular reactions and sensitivity to all-trans-retinoic acid (ATRA). SK-N-DZ cells expressed relatively high levels of retinoic acid receptor alpha (RAR-alpha) and underwent ATRA-induced cell death that was blocked by an RAR-alpha antagonist. By contrast, RAR-alpha expression gradually decreased in NH12 and SK-N-SH cells, which did not experience increased cell death in response to ATRA. We report here the ubiquitin-dependent down-regulation of RAR-alpha expression during ATRA treatment. Our data suggest that SK-N-DZ cells have a defect in RAR-alpha down-regulation, resulting in sustained high expression of RAR-alpha that confers high sensitivity to ATRA. Accordingly, treatment with a proteasome inhibitor dramatically increased ATRA-induced cell death in NH12 and SK-N-SH cell lines. Our results reveal the crucial involvement of the RAR-alpha signaling pathway in NBL cell death and show that three NBL cell lines are differentially sensitive to ATRA. These data suggest a potential novel therapy for NBL involving retinoic acid treatment combined with the inhibition of RAR-alpha degradation.
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PMID:Retinoic acid induces neuroblastoma cell death by inhibiting proteasomal degradation of retinoic acid receptor alpha. 1552 Jan 97

Xeroderma pigmentosum group A (XPA)-binding protein 2 (XAB2) is composed of 855 amino acids, contains 15 tetratricopeptide repeat motifs, and associates with Cockayne syndrome group A and B proteins and RNA polymerase II, as well as XPA. In vitro and in vivo studies showed that XAB2 is involved in pre-mRNA splicing, transcription, and transcription-coupled DNA repair, leading to preimplantation lethality, and is essential for mouse embryogenesis. Retinoids are effective for the treatment of preneoplastic diseases including xeroderma pigmentosum and other dermatologic diseases such as photoaging. We therefore focused on defining the effect of XAB2 on cellular differentiation in the presence of ATRA treatment. In the present study, we showed that overexpression of XAB2 inhibited ATRA-induced cellular differentiation in human rhabdomyosarcoma cell line, and that knockdown of XAB2 by small interfering RNA (siRNA) increased ATRA-sensitive cellular differentiation in the human promyelocytic leukemia cell line HL60 at both physiologic (10(-9)-10(-8) mol/L) and therapeutic (10(-7) mol/L) concentrations of ATRA. Moreover, we found that XAB2 was associated with retinoic acid receptor alpha (RARalpha) and histone deacetylase 3 in the nuclei. Finally, using siRNA against XAB2, we showed that the ATRA-resistant neuroblastoma cell line IMR-32 underwent cellular differentiation induced by ATRA at a therapeutic concentration (10(-6) mol/L). These results strongly suggest that XAB2 is a component of the RAR corepressor complex with an inhibitory effect on ATRA-induced cellular differentiation and that XAB2 plays a role in ATRA-mediated cellular differentiation as an important aspect of cancer therapy.
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PMID:Knockdown of XAB2 enhances all-trans retinoic acid-induced cellular differentiation in all-trans retinoic acid-sensitive and -resistant cancer cells. 1728 34

Monoamine oxidase (MAO) B deaminates a number of biogenic and dietary amines and plays an important role in many biological processes. Among hormonal regulations of MAO B, we have recently found that retinoic acid (RA) significantly activates both MAO B promoter activity and mRNA expression in a human neuroblastoma BE(2)C cell line. RA activates MAO B promoter in both concentration- and time-dependent manners, which is mediated through retinoic acid receptor alpha (RARalpha) and retinoid X receptor alpha (RXRalpha). There are four retinoic acid response elements (RAREs) as identified in the MAO B 2-kb promoter, and mutation of the third RARE reduced RA-induced MAO B promoter activation by 50%, suggesting this element is important. Electrophoretic mobility shift analysis and chromatin immunoprecipitation assay demonstrated that RARalpha specifically binds to the third RARE both in vitro and in vivo. Moreover, transient transfection and luciferase assays revealed that Sp1 enhances but not essentially required for the RA activation of MAO B through two clusters of Sp1-binding sites in the MAO B promoter. RARalpha physically interacts with Sp1 via zinc finger domains in Sp1 as determined by co-immunoprecipitation assay. Further, RARalpha was shown to be recruited by Sp1 and to form a transcriptional regulation complex with Sp1 in the Sp1-binding sites of natural MAO B promoter. Taken together, this study provides evidence for the first time showing the stimulating effect of RA on MAO B and new insight into the molecular mechanisms of MAO B regulation by hormones.
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PMID:Retinoic acid activates monoamine oxidase B promoter in human neuronal cells. 1940 66


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