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)

Neuron-restrictive silencer factor (NRSF), also known as repressor element RE1 binding transcription factor (REST) or repressor binding to the X2 box (XBR) (REST/NRSF/XBR), is a zinc finger transcription factor that during early embryogenesis is required to repress a subset of neuron-specific genes in non-neural tissues and undifferentiated neural precursors. We have previously shown that splicing within the coding region of rat REST/NRSF/XBR (rREST) generates several different transcripts all of which are expressed in the adult nervous system. rREST transcripts with short neuron-specific exons (exon N) have in-frame stop codons and encode truncated proteins which have an N-terminal repressor domain and weakened DNA binding activity. The aim of this study was to analyze the regulatory mechanisms underlying REST/NRSF/XBR activity in human and mouse as compared to rat. We show that the structure of REST/NRSF/XBR gene and its regulation by neuron-specific splicing is conserved in human, mouse and rat. Expression levels of REST/NRSF/XBR transcripts with the insertion of exon N are increased during the neuronal differentiation of mouse teratocarcinoma PCC7 and rat pheocromocytoma PC12 cells and are high in several human and mouse neuroblastoma cells as compared to the relatively low levels in the developing and adult nervous system. The exclusive expression of the neuronal forms of REST/NRSF/XBR mRNAs in mouse neuroblastoma Neuro-2A cells is not caused by rearrangement of the REST/NRSF/XBR gene nor by mutations in the sequence of the splice sites flanking exon N. These data suggest that changes in REST/NRSF/XBR splicing pattern may result from altered levels of splicing factors reflecting the formation and/or progression of neuroblastoma tumors.
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PMID:Neuron-specific splicing of zinc finger transcription factor REST/NRSF/XBR is frequent in neuroblastomas and conserved in human, mouse and rat. 1052 96

Neurite outgrowth involves various molecular mechanisms generating complex brain connections. These mechanisms have been linked to plasticity and learning and are thought to be deregulated in neuropsychiatric diseases. The transcription factor REST/NRSF regulates a subset of genes encoding neurite outgrowth molecules. We demonstrate here the downregulation of Rest/Nrsf expression in a mouse neuroblastoma cell line. This downregulation induced a clear increase in neurite length. Quantitative polymerase chain reaction showed deregulation of the candidate genes L1cam, Elmo2, Ulip1 and Ulip2. These genes are bona fide candidates known to be involved in dendrite and axonal outgrowth. This approach could be adapted to high-throughput techniques for determination of the mammalian neurite outgrowth gene repertoire.
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PMID:Nrsf silencing induces molecular and subcellular changes linked to neuronal plasticity. 1749

The second human beta-galactoside alpha-2,6-sialyltransferase (hST6Gal II) differs from hST6Gal I, the first member of ST6Gal family, in substrate specificity and tissue expression pattern. While ST6GAL1 gene is expressed in almost all human tissues, ST6GAL2 shows a restricted tissue-specific pattern of expression, mostly expressed in embryonic and adult brain. In order to understand the mechanisms involved in the transcriptional regulation of ST6GAL2, we first characterized the transcription start sites (TSS) in SH-SY5Y neuroblastoma cells. 5' RACE experiments revealed multiple TSS located on three first alternative 5' exons, termed EX, EY and EZ, which are unusually close on the genomic sequence and are all located more than 42 kbp upstream of the first common coding exon. Using Taqman duplex Q-PCR, we showed that the ST6GAL2 transcripts initiated by EX or EY are mainly expressed in both brain-related cell lines and human cerebral cortex, testifying for the use of a similar transcriptional regulation in vivo. Furthermore, we also showed for the first time hST6Gal II protein expression in the different lobes of the human cortex. Luciferase reporter assays allowed us to define two sequences upstream EX and EY with a high and moderate promoter activity, respectively. Bioinformatics analysis and site-directed mutagenesis showed that NF-kappaB and NRSF are likely to act as transcriptional repressors, whereas neuronal-related development factors Sox5, Puralpha and Olf1, are likely to act as transcriptional activators of ST6GAL2. This suggests that ST6GAL2 transcription could be potentially activated for specific neuronal functions.
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PMID:Transcriptional regulation of the human ST6GAL2 gene in cerebral cortex and neuronal cells. 1976 37

miRNAs play key roles in the nervous system, where they mark distinct developmental stages. Accordingly, dysregulation of miRNA expression may have profound effects on neuronal physiology and pathology, including cancer. Among the neuronal miRNAs, miR-9 was shown to be upregulated during in vitro neuronal differentiation and downregulated in 50% of primary neuroblastoma tumors, suggesting a potential function as an oncosuppressor gene. In this study we characterized the promoter and the transcriptional regulation of the miR-9-2 gene during neuronal differentiation. We found that, despite its localization inside an exon of a putative host-gene, miR-9-2 is expressed as an independent unit with the promoter located in the upstream intron. By promoter fusion and mutational analyses, together with RNAi and Chromatin immunoprecipitation assays, we demonstrated that the concerted action of the master transcriptional factors RE1-silencing transcription factor (REST) and cAMP-response element binding protein (CREB) on miR-9-2 promoter induces miRNA expression during differentiation. We showed that the repressor REST inhibits the activity of the miR-9-2 promoter in undifferentiated neuroblastoma cells, whereas REST dismissal and phosphorylation of CREB trigger transcription in differentiating cells. Finally, a regulatory feed-back mechanism, in which the reciprocal action of miR-9 and REST may be relevant for the maintenance of the neuronal differentiation program, is shown.
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PMID:A minicircuitry involving REST and CREB controls miR-9-2 expression during human neuronal differentiation. 2062 18

A rapid drop of the transcription repressor REST/NRSF during precursor differentiation into nerve cells is known to release the repression of hundreds of specific genes and thus to orchestrate the acquisition of the specific phenotype. REST, however, is important not only for differentiation, but also for the maintenance of key properties in mature nerve cell. The PC12 line is uniquely favorable for studying REST because, in addition to the wild-type, low REST neurosecretory cells, it includes spontaneously defective clones lacking neurosecretion, where REST is as high as in non-nerve cells. In this article, we summarize our cell biologic studies of two nerve cell-specific processes dependent on REST, neurosecretion and neurite outgrowth. We demonstrate that, in wild-type PC12 transfected with REST constructs, expression of genes encoding proteins of dense-core and synaptic-like vesicles is decreased, though, to different extents, with chromogranins being the most and the SNAREs (except SNAP25) the least affected. Concomitantly, dense core-vesicles decrease markedly in size but can still be discharged by regulated exocytosis. When, in contrast, dominant-negative constructs of REST are transfected in high-REST PC12, and the main effector enzymes of REST, histone deacetylases, are blocked, dense-core vesicles reappear and are discharged upon stimulation. In high-REST PC12, also neurite outgrowth is inhibited by down regulation of the NGF receptor. Concomitantly, however, high REST induces the expression of proteins and of an exocytic organelle, the enlargeosome, which sustain a Rac1-dependent form of neurite outgrowth, unknown until now, operative in PC12, in neuroblastoma SH-SY5Y cells, and also in neurons.
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PMID:In PC12 cells, expression of neurosecretion and neurite outgrowth are governed by the transcription repressor REST/NRSF. 2104 48

REST/NRSF (the RE-1 silencing transcription factor or neuron-restrictive silencer factor) was originally identified as a transcriptional repressor of a number of neuronal-specific genes in neural stem cells and non-neuronal cells. REST functions as a master regulator in the maintenance of neural stem cells. During tumorigenesis, REST shows opposing roles in different type of cells. In human epithelial cancers such as colon cancer, REST acts as a tumor suppressor. In contrast, REST plays an oncogenic role in the development of brain tumors and other cancers. Abnormal upregulation of REST has been found in medulloblastoma, neuroblastoma and glioblastoma (GBM). Recent studies in GBMs suggest that REST exerts its oncogenic function by maintaining self-renewal potential of glioma stem cells (GSCs).
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PMID:Ubiquitination and deubiquitination of REST and its roles in cancers. 2256 92

The Repressor Element 1 Silencing Transcription factor (REST/NRSF) is a master repressor of neuronal programs in non-neuronal lineages shown to function as a central regulator of developmental programs and stem cell physiology. Aberrant REST function has been associated with a number of pathological conditions. In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma. Here we examined REST expression in human glioblastoma multiforme (GBM) specimens and its role in GBM cells carrying self-renewal and tumorigenic competence. We found REST to be expressed in GBM specimens, its presence being particularly enriched in tumor cells in the perivascular compartment. Significantly, REST is highly expressed in self-renewing tumorigenic-competent GBM cells and its knock down strongly reduces their self-renewal in vitro and tumor-initiating capacity in vivo and affects levels of miR-124 and its downstream targets. These results indicate that REST contributes to GBM maintenance by affecting its self-renewing and tumorigenic cellular component and that, hence, a better understanding of these circuitries in these cells might lead to new exploitable therapeutic targets.
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PMID:REST controls self-renewal and tumorigenic competence of human glioblastoma cells. 2640 2

The development and function of the nervous system are directly dependent on a well defined pattern of gene expression. Indeed, perturbation of transcriptional activity or epigenetic modifications of chromatin can dramatically influence neuronal phenotypes. The phosphoprotein synapsin I (Syn I) plays a crucial role during axonogenesis and synaptogenesis as well as in synaptic transmission and plasticity of mature neurons. Abnormalities in SYN1 gene expression have been linked to important neuropsychiatric disorders, such as epilepsy and autism. SYN1 gene transcription is suppressed in non-neural tissues by the RE1-silencing transcription factor (REST); however, the molecular mechanisms that allow the constitutive expression of this genetic region in neurons have not been clarified yet. Herein we demonstrate that a conserved region of human and mouse SYN1 promoters contains cis-sites for the transcriptional activator Sp1 in close proximity to REST binding motifs. Through a series of functional assays, we demonstrate a physical interaction of Sp1 on the SYN1 promoter and show that REST directly inhibits Sp1-mediated transcription, resulting in SYN1 down-regulation. Upon differentiation of neuroblastoma Neuro2a cells, we observe a decrease in endogenous REST and a higher stability of Sp1 on target GC boxes, resulting in an increase of SYN1 transcription. Moreover, methylation of Sp1 cis-sites in the SYN1 promoter region could provide an additional level of transcriptional regulation. Our results introduce Sp1 as a fundamental activator of basal SYN1 gene expression, whose activity is modulated by the neural master regulator REST and CpG methylation.
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PMID:Specificity protein 1 (Sp1)-dependent activation of the synapsin I gene (SYN1) is modulated by RE1-silencing transcription factor (REST) and 5'-cytosine-phosphoguanine (CpG) methylation. 2325 Jul 96

Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors.
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PMID:The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation. 2551 50