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

Retinoids are known to have profound effects on cellular differentiation and embryo pattern formation. In the adult organism, retinoid acid (RA) receptors are present in a large variety of tissues, including brain. However, little is known of the precise roles of RA at these different sites. In the present study we have identified a novel potential target of RA action by identifying an RA response element (RARE) in the human oxytocin (OT) gene promoter. We have used DNA-mediated gene transfer techniques to introduce various portions of the OT 5'-flanking sequences next to the chloramphenicol acetyltransferase (CAT) gene in neuroblastoma cells. RA elicited a marked stimulation of the transcriptional activity of the OT promoter in cells cotransfected with either the human RA receptor alpha, beta, or gamma. In cells cotransfected with the RA receptor alpha, the ED50 of this response was 5 x 10(-10) M. The RA response could also be conferred to a heterologous promoter independent of orientation. 5'-Deletions as well as site-directed mutations demonstrated that four TGACC motifs, located at -162, -156, -103, and -83 in the OT promoter, are necessary for optimal RA induction. Mutation or deletion of any of these elements reduces significantly the RA response. Interestingly, the first two TGACC motifs overlap with the estrogen response element that we have previously characterized in this gene. Furthermore, the TGACC motif located at -83 overlaps with the CCAAT box. We further demonstrate that in neuroblastoma cells transfected with an RAR alpha expression vector expression of the endogenous OT gene is stimulated greater than 4-fold in response to RA. Our studies constitute the first report of a RARE in a neuropeptide gene and define a mechanism by which OT gene expression can be modulated by retinoic acid.
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PMID:Identification of a retinoic acid response element in the human oxytocin promoter. 165 67

Two families of nuclear retinoid receptors, retinoic acid receptor and retinoid X receptor (RAR and RXR respectively), and a family of cellular retinoic acid-binding proteins (CRABPI and II) participate in the retinoic acid (RA) signaling pathway. The presence and function of many of these receptors and cellular binding proteins have not been fully explored in RA-responsive human neuroblastoma cells. We have previously shown that RAR transcripts and protein are present in human neuroblastoma cells, and that all-trans RA induces the expression of the RAR beta mRNA. In this paper, we demonstrate that human neuroblastoma cells express mRNA for RXR alpha and beta. The mRNA for CRABPI is present in untreated human neuroblastoma cells, whereas the mRNA for CRABPII is induced in cells treated with either all-trans RA or 9-cis RA. Furthermore, 9-cis RA, a ligand that binds to both the RAR and the RXR families, selectively activates the CRABPII gene. In contrast, all-trans RA and 9-cis RA are equally effective in the induction of RAR beta transcript and inhibition of cell proliferation. Since both retinoids inhibit human neuroblastoma cell proliferation, it appears that induction of RAR beta rather than of CRABPII is more likely linked to the regulation of human neuroblastoma cell growth.
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PMID:9-cis-retinoic acid selectively activates the cellular retinoic acid binding protein-II gene in human neuroblastoma cells. 778 28

Phenylacetate, a natural metabolite of phenylalanine which was originally described as a plant growth hormone, has recently gained attention as a possible differentiation inducer for a variety of human tumor cell types. This interest prompted us to assess the ability of sodium phenylacetate (NaPA) to promote the differentiation of human neuroblastoma cells, both alone and in combination with retinoic acid (RA), a known inducer of neuroblastoma differentiation and maturation. Using the LA-N-5 cell line, we have determined that NaPA can stimulate the differentiation of neuroblastoma cells, as evidenced by dose-dependent inhibition of cell proliferation, neurite outgrowth, increased acetylcholinesterase activity and reduction of N-myc expression. Furthermore, NaPA and RA synergized in inducing differentiation, in that combination treatment resulted in cessation of cell growth along with morphologic and biochemical changes indicative of the loss of malignant properties. We have determined that NaPA can markedly enhance mRNA levels of the nuclear RA receptor-beta (RAR beta) in LA-N-5 cells prior to morphologic or other phenotypic changes induced by this compound. This effect appeared to be distinct from the ability of NaPA to alter tumor cell lipid metabolism via inhibition of protein isoprenylation. Thus among its varied effects on LA-N-5 cells, NaPA appears to interact with the RA pathway at the nuclear level by up-regulating RAR beta expression.
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PMID:Phenylacetate synergizes with retinoic acid in inducing the differentiation of human neuroblastoma cells. 782 65

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

Retinoic acid (RA) nuclear receptors (RARs) are thought to mediate the cellular and molecular effects of RA on a wide variety of tissues. In most cell types, RAR alpha expression remains relatively constant following exposure to RA, while that of RAR beta is rapidly induced. In this study, we show that in human neuroblastoma, a cell type exceptionally sensitive to RA-induced differentiation, RAR alpha as well as RAR beta is markedly up-regulated by RA treatment. This effect was consistent in all 5 neuroblastoma cell lines tested and was reflected in a 2- to 5-fold increase in receptor mRNA levels as assessed by Northern-blot analysis. Using LA-N-5 human neuroblastoma cells, we found that receptor up-regulation occurred in a time- and dose-dependent fashion with increases in both RAR alpha and beta mRNA detectable 1-2 hr after the addition of RA. These inductions were not abrogated by cycloheximide, indicating that protein synthesis was not required for the RA responses. Nuclear run-off experiments combined with Northern-blot analysis of RAR alpha stability directly demonstrated that the up-regulation of RAR alpha mRNA levels reflected an increased rate of transcription without changes in message half-life. These findings, showing direct activation by RA of RAR alpha gene transcription in human neuroblastoma cells, suggest differences in the overall regulation of this receptor from that found in most other RA-inducible tissue.
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PMID:Retinoic acid up-regulates nuclear retinoic acid receptor-alpha expression in human neuroblastoma cells. 811 74

Retinoic acid (RA) induces growth inhibition, differentiation or cell death in many human neuroblastoma cell lines. Recently, the transactivation activity of nuclear retinoids receptors has been shown to be modulated through physical association with other proteins that act as co-activators or as co-repressors. We investigated the expression of the co-repressor (SMRT) and co-activator (Trip 1) for retinoid and thyroid-hormone receptors in several neuroectodermal tumour cell lines, and its modulation by all-trans-retinoic acid, as well as by synthetic agonists, for RAR alpha, RAR beta, RAR gamma and RXR. We demonstrate that (i) SMRT and Trip-1 mRNAs are expressed in many human neuroblastoma and melanoma cell lines in basal conditions, (ii) SMRT mRNA expression in human neuroblastoma cell line SK-N-BE(2) increases after 48 hours of incubation with 1 microM RA and RARs specific agonists, (iii) Trip-1 mRNA in the same cell line does not change during incubation with RA or selective synthetic agonists for RARs and RXR.
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PMID:Expression of co-factors (SMRT and Trip-1) for retinoic acid receptors in human neuroectodermal cell lines. 916 3

All-trans retinoic acid (RA) reduces human neuroblastoma growth by inducing either differentiation or apoptosis. The apoptotic program in these cells is regulated by RA and is paralleled by the transcriptional induction of "tissue" transglutaminase (tTG). tTG is a protein cross-linking enzyme, which specifically accumulates in cells undergoing apoptosis in various in vivo and in vitro systems. In neuroblastoma cells, tTG is detected exclusively in the cells expressing the S-type phenotype and showing an increased apoptosis. The present study was undertaken to identify the retinoid receptors which are involved in the regulation of tTG and apoptosis as well as in the in vitro neuronal differentiation of the human SK-N-BE(2) neuroblastoma cell line. We have previously characterized the retinoid acid receptors expressed in this cell line. In the present study, by using synthetic retinoids selectively activating RAR/RXR isoforms, we have identified the RAR/RXR receptors involved in the induction of either apoptosis or differentiation. We have also studied the effect of the selective RA analogs on tTG activity. We observed that while RARalpha- and RARgamma-selective retinoids alone were able to induce tTG activity, only the combined stimulation of both RARalpha and RARgamma induced apoptosis. Conversely, several combinations of RAR/RXR closely mimicked the differentiation effects observed with all-trans retinoic acid. These results indicate that, at variance with differentiation, the induction of apoptosis in human SK-N-BE(2) neuroblastoma cells is under the specific control of RARalpha and RARgamma. These data seem relevant for the reported ability of RARgamma to suppress the clinically malignant tumor phenotype in patients.
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PMID:Retinoic acid receptors alpha and gamma mediate the induction of "tissue" transglutaminase activity and apoptosis in human neuroblastoma cells. 928 52

Retinoic acid (RA) plays a major role in embryogenesis of the nervous system and has been reported to induce differentiation in neuroblastoma cell lines. To identify RA signaling pathways involved in such differentiation processes, two RA-sensitive neuroblastoma cell lines (LA-N-5 and SH-SY5Y) were extensively studied. Northern blot experiments determined that of the three RAR mRNAs, only RARalpha was significantly expressed, with respectively weak or undetectable levels of RARgamma and RARbeta. RXRs (alpha and beta) receptors were weakly expressed. Western blotting analysis confirmed the constitutive expression of RARalpha and absence of RARbeta and weak levels of RXRalpha. Treatment with all-trans-RA up-regulated RARalpha and induced a drastic increase of RARbeta (both at the RNA and protein level). To further characterize the function of RARalpha, RARbeta and RXRalpha in NB cells, nuclear extracts from LA-N-5 cells were analysed by EMSA studies. Three specific retarded complexes were observed which were significantly decreased or shifted in the presence of monoclonal antibodies to RARalpha, RARbeta and RXRalpha. RA treatment dramatically induced a DR5-binding RXRalpha-RARbeta heterodimer. Treatment with combinations of RARalpha or RARbeta agonists with a RXRalpha agonist or with a RARalpha agonist alone, induced neurite-outgrowth supporting the probability that both RXRalpha-RARalpha or RXRalpha-RARbeta heterodimers are involved in RA-mediated differentiation of NB cells. The availability of novel synthetic RA-specific receptor ligands should provide the possibility of tissue specific therapeutic regimes.
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PMID:Distinct sensitivity of neuroblastoma cells for retinoid receptor agonists: evidence for functional receptor heterodimers. 936 47

Sodium phenylacetate (NaPA) has been shown to synergize with retinoic acid (RA) in inducing the differentiation of human neuroblastoma cells. Our studies indicated that NaPA can impact on the RA differentiation program by upregulating nuclear retinoic acid receptor-beta (RAR beta) expression. We have found that NaPA does not alter the half-life of RAR beta mRNA; thus, increased stability of mRNA levels does not contribute to NaPA induction. In contrast, NaPA was able to specifically activate a reporter gene construct (delta SV beta RE-CAT) which contains a retinoic acid response element (RARE beta) that is located in the RAR beta promoter. Activation of delta SV beta RE-CAT by NaPA also occurred in neuroblastoma cells cotransfected with a nuclear retinoic acid receptor expression vector, demonstrating the independence of this activation on cellular RAR levels. Taken together, our findings suggest that induction of RAR beta by NaPA is regulated at the level of transcription and mediated through the retinoic acid response element, RARE beta. This effect may account, at least in part, for the strong synergy between NaPA and RA in promoting neuroblastoma differentiation.
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PMID:Transcriptional upregulation of retinoic acid receptor beta (RAR beta) expression by phenylacetate in human neuroblastoma cells. 951 35


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