Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal. The pattern of retinoid responsiveness for six of 13 target genes (RARbeta2, CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic retinoid sensitivity, across a panel of retinoid-sensitive or -resistant lung and breast cancer cell lines. Retinoid treatment of MYCN transgenic mice bearing neuroblastoma altered the expression of five of nine target genes examined (RARbeta2, CYP26A1, CRBP1, DUSP6, PLAT) in neuroblastoma tumour tissue in vivo. In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARbeta2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARbeta2 partially restored retinoid-responsive CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1 lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block retinoid-induced growth inhibition in neuroblastoma cells, through phosphorylation of extracellular-signal-regulated kinase. In conclusion, sensitivity to the retinoid anticancer signal is determined in part by the transcriptional response of key retinoid-regulated target genes, such as RARbeta2, DUSP6, and RGS16.
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PMID:The retinoid anticancer signal: mechanisms of target gene regulation. 1601 19

DNA damage and activation of the cell cycle have been implicated in numerous neurodegenerative diseases, including Alzheimer disease, Parkinson's disease, and amyotrophic lateral sclerosis. To better understand the role of cell cycle proteins in DNA-damage induced neuronal cell death, we examined various cell cycle proteins during camptothecin-induced death of human neuroblastoma cells. We report a rapid induction of p53 and increased expression of p21, concurrent with reduced levels of many cell cycle proteins that regulate G1 to S phase cell cycle progression. However, we found increased levels of cdk2 and cyclin E, and formation of a cyclin E-cdk2-p21 protein complex. DNA damage failed to induce activation and progression of the cell cycle. Finally, camptothecin-induced neuronal cell death occurred concurrent with phosphorylation of histone H2B. Pretreatment of cells with cdk inhibitor olomoucine impeded cdk2-cyclin E accumulation, but not the induction of p53. Olomucine concurrently delayed histone H2B phosphorylation, caspase-3 activation and cell death. These findings suggest that DNA-damage of differentiated neuroblastoma cells induces a rapid p53-mediated inhibition of cell cycle progression and induction of cdk2-cyclin E, followed by caspase-3 activation, phosphorylation of histone and cell death.
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PMID:DNA damage induces cdk2 protein levels and histone H2B phosphorylation in SH-SY5Y neuroblastoma cells. 1615 45

Telomeres are specialized structures at the ends of chromosomes that consist of tandem repeats of the DNA sequence TTAGGG and several proteins that protect the DNA and regulate the plasticity of the telomeres. The telomere-associated protein TRF2 (telomeric repeat binding factor 2) is critical for the control of telomere structure and function; TRF2 dysfunction results in the exposure of the telomere ends and activation of ATM (ataxia telangiectasin mutated)-mediated DNA damage response. Recent findings suggest that telomere attrition can cause senescence or apoptosis of mitotic cells, but the function of telomeres in differentiated neurons is unknown. Here, we examined the impact of telomere dysfunction via TRF2 inhibition in neurons (primary embryonic hippocampal neurons) and mitotic neural cells (astrocytes and neuroblastoma cells). We demonstrate that telomere dysfunction induced by adenovirus-mediated expression of dominant-negative TRF2 (DN-TRF2) triggers a DNA damage response involving the formation of nuclear foci containing phosphorylated histone H2AX and activated ATM in each cell type. In mitotic neural cells DN-TRF2 induced activation of both p53 and p21 and senescence (as indicated by an up-regulation of beta-galactosidase). In contrast, in neurons DN-TRF2 increased p21, but neither p53 nor beta-galactosidase was induced. In addition, TRF2 inhibition enhanced the morphological, molecular and biophysical differentiation of hippocampal neurons. These findings demonstrate divergent molecular and physiological responses to telomere dysfunction in mitotic neural cells and neurons, indicate a role for TRF2 in regulating neuronal differentiation, and suggest a potential therapeutic application of inhibition of TRF2 function in the treatment of neural tumors.
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PMID:TRF2 dysfunction elicits DNA damage responses associated with senescence in proliferating neural cells and differentiation of neurons. 1653 55

Starting from the high affinity sigma(2) receptor ligand 2, (PB28), we synthesized amino derivative 4 and coupled it to an NHS-ester activated sepharose stationary phase column to elute a crude protein prepared by lysed human SK-N-SH neuroblastoma cells. We characterized the SDS-PAGE gel electrophoresis stained bands by MALDI-MS and LC-MS-MS analysis. The MASCOT MS-MS ion search program led to the identification of the protein components. The six eluted proteins had a molecular weight ranging from 13 kDa to 26 kDa and were human histone proteins. A human 40S ribosomal protein S3 (SwissProt accession number: P23396) was also identified as a comigrated band. The human histone proteins that were characterized were H3.3A histone (NCBI accession number: 51859376), H2B histone (NCBI accession number: 1568557), H2A.5 histone (NCBI accession number: 70686), H1 (NCBI accession number: 22770677), and H2.1 histone (SwissProt accession number: P16403). These results disclosed a dual hypothesis about the sigma(2) receptor, that is, that it is formed by histones or that the sigma(2) ligands also bind histone proteins.
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PMID:Is the sigma2 receptor a histone binding protein? 1682 75

Nociceptin/orphanin FQ (NOP/OFQ) is the endogenous ligand for the NOP receptor and is processed from a precursor protein in the family of opioid peptides. Prepronociceptin (ppN/OFQ) mRNA has been shown to be upregulated by an increase in cAMP, a treatment that leads to differentiation of NS20Y neuroblastoma cells. Although a large increase in endogenous ppN/OFQ mRNA upon cAMP stimulation can be shown in cellular systems, a similar increase cannot be expressed in pGL3 luciferase vector containing 1.3 kb proximal promoter, suggesting that a larger portion of the sequence or a different chromatin structure is necessary for a fully functional promoter. The induction of ppN/OFQ mRNA by cAMP appears to be mediated by a cAMP-response element. Chromatin immunoprecipitation (ChIP) assays show that CREB is recruited to the promoter region upon treatment of NS20Y cells with dibutyryl cAMP. In addition, the production of ppN/OFQ mRNA is regulated by histone acetylation, also through CREB, as the histone deacetylase (HDAC) inhibitor trichostatin A increases both CREB binding to the promoter and ppN/OFQ mRNA expression. In rat progenitor and mouse neuroblastoma cell lines, agents that increase ppN/OFQ mRNA expression also induce neurite outgrowth, suggesting a close relationship between ppN/OFQ and cellular differentiation.
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PMID:Regulation of the prepronociceptin gene and its effect on neuronal differentiation. 1693 38

We previously identified a 1.2 Kb DNA element (P-1161/+16), 5' to caspase-8 exon-1, that acts as promoter in caspase-8-positive, but not in caspase-8-negative neuroblastoma (NB) cells. The P-1161/+16 DNA element regulates both constitutive and interferon IFN-gamma-inducible caspase-8 expression. Two GAS (IFN-activated sequence, STAT-1 binding site) and two ISRE (interferon sensitive response element, IRF binding site) were present in P-1161/+16. Deletion studies indicated that elements essential for promoter activity in NB cells were present in a 167 bp region 5' flanking exon-1 (P-151/+16), which contains an ISRE at position -32. The transcription initiation site was mapped by 5' rapid amplification of cDNA end (RACE) at position -20 from caspase-8 cDNA reference sequence. Disruption of the ISRE-32 indicated that it is required for both constitutive and IFN-gamma-inducible caspase-8 expression. IRF-1 and IRF-2 transcription factors bind to the (-151/+16) DNA fragment in vitro. Chromatin immunoprecipitation (ChIP) assays showed that IRF-1 and IRF-2 bind to the DNA region at the 5' of caspase-8 gene in NB cells, which show constitutive expression but not in caspase-8 negative cells. In these last cells, up-regulation of caspase-8 by IFN-gamma was associated to induction of IRF-1 and IRF-2 binding to caspase-8 promoter and increased histone acetylation. Moreover, RNA interference experiments also supported the involvement of IRF-1 and IRF-2 in constitutive caspase-8 expression in NB cells.
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PMID:An interferon-sensitive response element is involved in constitutive caspase-8 gene expression in neuroblastoma cells. 1703 21

The transcriptional and chromatin profile of the promoter, first exon and first intron of the human TH gene were analyzed in human neuroblastoma BE(2)-C-16 and human renal carcinoma 293FT cell lines. The latter is a cell culture system that is not permissive for TH gene expression, whereas the former has a 50% cell fraction that tests positive for TH. The engineering of a 6.3 kb recombinant human TH promoter revealed the presence of repressors of transcription between positions (-6,244/-194). The addition of a 1.2 kb fragment of the first intron of the human TH gene (+730/+1,653) enhanced transcriptional activity of the recombinant promoter. However, both constructs were not specific for TH-positive BE(2)-C-16 cells. Chromatin immunoprecipitation (Chip) analysis was carried out on BE(2)-C-16 and 293FT cells to probe sequences of promoter, first exon and first intron of the human TH gene from position (-448/+1,204). The presence of nucleosomes was observed approximately from position (-20/+473) in both cell lines. Chip analysis was then conducted to determine the acetylation of various lysine residues of H3 and H4 in both cell lines. All analyzed lysine residues of H3 and H4 were acetylated in BE(2)-C-16 cells, whereas 293FT cells tested positive for acetylation only in the external lysine residues of the histone tail. Our data are compatible with an active TH gene expression in a 50% cell fraction of BE(2)-C-16 cells. Further analysis of epigenetic programming might lead to the identification of the factors that determine TH gene expression specifically in dopaminergic neurons.
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PMID:Transcription and epigenetic profile of the promoter, first exon and first intron of the human tyrosine hydroxylase gene. 1719 53

Recent progress in molecular biology has led to an increase of prognostic markers and development of molecular-targeted therapy in pediatric malignancies. Previous treatment including stem cell transplantation showed a remarkable cure rate, however, some patients are resistant to such therapy. Recently, all-trans retinoic acid (ATRA) for acute promyeloblastic leukemia, imatinib for chronic myeloid leukemia, and rituximab for B-cell malignant lymphoma serve to improve the clinical outcome of these patients. Furthermore, molecular-targeted therapies including tyrosine kinase inhibitor, farnesyl transferase inhibitor, methylation inhibitor, and histone deacetyl enzyme inhibitor, were applied for clinical study. For pediatric malignancies, in addition to molecular-targeted therapy against leukemia, molecular-targeted therapies, mainly tyrosin kinase inhibitors, were applied to neuroblastoma and various types of sarcomas. Recent progress in prognostic molecular marker and molecular-targeted therapy against pediatric malignancies was here reviewed.
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PMID:[Prognostic molecular marker and molecular targeted-therapy in pediatric malignancies]. 1730 26

Chromosome 1p is frequently deleted in neuroblastoma (NB) tumours. The commonly deleted region has been narrowed down by loss of heterozygosity studies undertaken by different groups. Based on earlier mapping data, we have focused on a region on 1p36 (chr1: 7 765 595-11 019 814) and performed an analysis of 30 genes by exploring features such as epigenetic regulation, that is DNA methylation and histone deacetylation, mutations at the DNA level and mRNA expression. Treatment of NB cell lines with the histone deacetylase inhibitor trichostatin A led to increased gene transcription of four of the 30 genes, ERRFI1 (MIG-6), PIK3CD, RBP7 (CRBPIV) and CASZ1, indicating that these genes could be affected by epigenetic downregulation in NBs. Two patients with nonsynonymous mutations in the PIK3CD gene were detected. One patient harboured three variations in the same exon, and p.R188W. The other patient had the variation p.M655I. In addition, synonymous variations and one variation in an intronic sequence were also found. The mRNA expression of this gene is downregulated in unfavourable, compared to favourable, NBs. One nonsynonymous mutation was also identified in the ERRFI1 gene, p.N343S, and one synonymous. None of the variations above were found in healthy control individuals. In conclusion, of the 30 genes analysed, the PIK3CD gene stands out as one of the most interesting for further studies of NB development and progression.
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PMID:Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours. 1794 May 11

HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells. In general, increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels are linked to repression of gene expression. HDACs associate with a number of cellular oncogenes and tumour-suppressor genes, leading to an aberrant recruitment of HDAC activity, which results in changes of gene expression, impaired differentiation and excessive proliferation of tumour cells. Therefore HDAC inhibitors are efficient anti-proliferative agents in both in vitro and in vivo pre-clinical models of cancer, making them promising anticancer therapeutics. In the present paper, we present the results of a medium-throughput screening programme aiming at the identification of novel HDAC inhibitors using HDAH (HDAC-like amidohydrolase) from Bordetella or Alcaligenes strain FB188 as a model enzyme. Within a library of 3719 compounds, several new classes of HDAC inhibitor were identified. Among these hit compounds, there were also potent inhibitors of eukaryotic HDACs, as demonstrated by an increase in histone H4 acetylation, accompanied by a decrease in tumour cell metabolism in both SHEP neuroblastoma and T24 bladder carcinoma cells. In conclusion, screening of a compound library using FB188 HDAH as model enzyme identified several promising new lead structures for further development.
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PMID:Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorigenic assay. 1838 90


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