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)

An important family of regulatory molecules is made up of proteins that possess the DNA-binding and dimerization motif known as the basic helix-loop-helix (bHLH) domain. The bHLH family includes subgroups of closely related proteins that share common functional properties and overlapping patterns of expression (e.g., the MyoD1 and achaete-scute subgroups). In this report we describe HEN1 and HEN2, mammalian genes that encode a distinct subgroup of bHLH proteins. The HEN1 gene was identified on the basis of cross-hybridization with TAL1, a known bHLH gene implicated in T-cell acute lymphoblastic leukemia. In situ fluorescence hybridization was used to localize the human HEN1 gene to chromosome band 1q22. HEN1 and HEN2 are coexpressed in the IMR-32 human neuroblastoma cell line, and they encode highly related proteins of 133 and 135 residues, respectively, that share 98% amino acid identity in their hHLH domains. These data imply that the bHLH protein subgroup encoded by HEN1 and HEN2 may serve important regulatory functions in the developing nervous system.
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PMID:HEN1 and HEN2: a subgroup of basic helix-loop-helix genes that are coexpressed in a human neuroblastoma. 152 53

HES-5 is a mammalian basic helix-loop-helix factor that has a distant sequence homology to the product of the Drosophila pair-rule gene hairy. HES-5 mRNA is present exclusively in the developing nervous system, but its level decreases as neural differentiation proceeds. In this study, to characterize the molecular mechanism of the neural-specific expression of HES-5 we isolated the mouse HES-5 gene. This gene consists of three exons, and Southern blot analysis shows that it is a single copy gene. The transcription initiation site, determined by primer extension and reverse transcriptase-mediated polymerase chain reaction, is located 26 nucleotides downstream of a TATAbox. Transient transfection analysis shows that the upstream region of the HES-5 gene can direct efficient expression in neural precursor cells and moderate expression in undifferentiated NCB20 neuroblastoma-brain hybrid cells but not in glioma or fibroblast cells. The moderate level of expression in NCB20 cells decreases when differentiation into neuron-like cells is induced. Further promoter analysis shows that this undifferentiated neural-specific expression is mediated by the multiple GC stretches present in the HES-5 promoter. Gel mobility shift analysis suggests the presence of a neural precursor cell-specific protein that binds to the GC stretches. These results raise the possibility that HES-5 expression in the developing nervous system is regulated by the GC stretch-binding protein.
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PMID:Structure and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-5. Identification of the neural precursor cell-specific promoter element. 783 1

One of the first oncogenes identified from human tumors was c-myc, which is frequently activated in Burkitt's lymphomas due to chromosomal translocations. Subsequently, members of the myc oncogene family were found to be amplified in neuroblastoma and small-cell lung cancer. In normal cells, Myc activity has been shown to be both necessary and sufficient for resting cells to enter the cell cycle. Interestingly, it appears that Myc not only drives the cell cycle, but also induces cell death by apoptosis in certain situations. Myc contains a transcriptional activation domain and a basic helix-loop-helix-leucine zipper DNA-binding and dimerization domain. As a heterodimer with a structurally related protein, Max, Myc can bind DNA in a sequence-specific manner. These results suggest that the Myc/Max heterodimer functions as a transcriptional activator of genes that are critical for the regulation of cell growth.
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PMID:Myc protein: partners and antagonists. 794 8

Myc proteins are basic helix-loop-helix/leucine-zipper proteins that bind to specific DNA sequences. In vivo, Myc proteins have been found associated with Max, another basic helix-loop-helix/leucine-zipper protein. However, it is not known to what extent the dimerization of Myc with Max is required for the manifestation of the Myc-induced phenotype. To investigate this, we constructed a dominant-negative mutant of Max, named dMax, that inhibits sequence-specific DNA binding of Myc proteins. Using a rat neuroblastoma model system, we show that dMax reverts N-Myc-induced changes in cellular gene expression. A control mutant of dMax that contains a proline residue in the leucine-zipper region was unable to bind to N-Myc and did not revert the N-Myc-induced changes in cellular gene expression. These data support the hypothesis that N-Myc affects neuroblastoma gene expression through the formation of a DNA-binding heterodimeric complex with Max in vivo.
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PMID:A dominant-negative mutant of Max that inhibits sequence-specific DNA binding by Myc proteins. 846 83

We have examined cis-elements and trans-acting factors that regulate transcription of the human cholecystokinin (CCK) gene. Transient expression of CCK promoter deletion constructs in human SK-N-MC neuroblastoma cells depicted positive cis-elements between the positions -100 to -92, -84 to -74, and -58 to -37, 5' to the transcription initiation site. Correspondingly, DNase I protection analysis showed that transacting factors bound to elements within these regions. The sequences encompass a putative basic helix-loop-helix leucine zipper (bHLH-ZIP) element, an Sp1 element, and a combined cAMP- and TPA-responsive element (CRE/TRE) at positions -97 to -92, -39 to -34, and -80 to -73, respectively. Mobility and supershift assays demonstrated that upstream stimulatory factor (USF) and Sp1 bind to the former elements and competition experiments confirmed that CREB/ATF and AP-1 bind to the CRE/TRE element. Mutation of the bHLH-ZIP and CRE/TRE elements decreased the activity of the promoter by 65% and 42%, respectively. The activity of the promoter was increased six- and two-fold after stimulation with forskolin and TPA, respectively. Stimulation was eliminated after mutation of the CRE/TRE element. Co-transfection experiments with pRSV-c-jun, pSV-fos, and pRC-RSV-CREB constructs showed that jun, CREB, and AP-1 stimulate transcription. We conclude that USF, Sp1, and members of the CREB/ATF and AP-1 family of transcription factors are the major determinants of CCK gene transcription.
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PMID:Transcriptional regulation of the human cholecystokinin gene: composite action of upstream stimulatory factor, Sp1, and members of the CREB/ATF-AP-1 family of transcription factors. 856 97

Several neuron-specific cDNAs were identified using large-scale collection of 3'-directed partial cDNA sequences from a human neuroblastoma cell line. One of such cDNAs encoded a protein homologous to the mouse NeuroD. The mouse NeuroD, a basic helix-loop-helix (bHLH) protein seems to function as a differentiation factor for neurogenesis, as the gene is transiently expressed in postmitoic differentiating neurons. The human counterpart has a bHLH domain completely identical to that of the mouse NeuroD. But its expression was not only in the fetal brain but also in the adult cerebellum. The result of cross-species in situ hybridization also showed the transcripts were detected in the granule cell layer of the adult mouse cerebellum. The results suggest that the human as well as the mouse neuroD may play some important functions not only in the fetal brain but also in the fetal brain but also in the matured neurons of the cerebellum.
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PMID:Molecular cloning of a human neuroD from a neuroblastoma cell line specifically expressed in the fetal brain and adult cerebellum. 891 91

The type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) is expressed abundantly in the CNS, such as in cerebellar Purkinje cells and the hippocampus. We established a tissue-specific cell-free transcription system and studied regulatory properties of the 5' upstream region of the IP3R1 gene by use of this system. Deletion analyses of the promoter revealed several cis elements that function significantly in brain nuclear extracts. Among those elements, sequences from -398 to -295 showed the most predominant cerebellum-specific positive function. Footprint analyses demonstrated a factor-binding region from -334 to -318, termed box-I, that contained an E-box consensus sequence. Electrophoretic mobility shift assay revealed CNS-related basic helix-loop-helix proteins for the box-I. Mutational studies using the function assay and competitive electrophoretic mobility shift assays demonstrated a good correlation between the box-I-binding factors and the activated transcription. Box-I-binding factors were present abundantly in adult mouse CNS, whereas their existence was restricted in embryonic and nonneural tissues. Transient chloramphenicol acetyltransferase assay for the IP3R1 promoter revealed the requirement of box-I in Neuro2a neuroblastoma cells. In the postnatal CNS, multiple basic helix-loop-helix factors are expressed abundantly, some of which are suggested to activate IP3R1 gene expression in the mammalian CNS.
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PMID:Demonstration of an E-box and its CNS-related binding factors for transcriptional regulation of the mouse type 1 inositol 1,4,5-trisphosphate receptor gene. 923 5

The basic helix-loop-helix (bHLH) class of transcription factors plays a pivotal role in tissue-specific determination and differentiation. Moreover, dysregulated expression or loss of function of these factors contributes to leukemogenesis and solid tumor development. Neurogenesis is regulated by genes of the NEUROD/atonal and ACHAETE SCUTE families. We analyzed expression of human NEUROD1, NEUROD2, NEUROD3, and ACHAETE SCUTE 1 (HASH1) in cerebellar and cerebral primitive neuroectodermal tumors (PNETs), gliomas, and cell lines derived from a variety of neuroectodermal tumors by Northern analysis and in situ hybridization. NEUROD1 was expressed in each of the 12 medulloblastoma specimens, whereas NEUROD2 and NEUROD3/neurogenin were expressed in partly overlapping subsets of medulloblastomas. All of the tumors that presented with distant metastases expressed NEUROD3. The only other NEUROD3-positive tumor progressed early in treatment. Human ACHAETE SCUTE homologue (HASH1) was not expressed in medulloblastomas (infratentorial PNETs) but was expressed in three of five supratentorial PNETs. Neuroectodermal tumor cell lines derived from other sites (e.g., neuroblastoma and retinoblastoma) expressed NeuroD and ACHAETE SCUTE family members. No NEUROD message was detected in glial tumors or cell lines. Neurogenic bHLH transcription factor expression patterns suggest that specific family members may contribute to or reflect biological differences that arise during malignant transformation.
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PMID:Expression of neurogenic basic helix-loop-helix genes in primitive neuroectodermal tumors. 927 24

ath3, a vertebrate basic helix-loop-helix gene homologous to Drosophila proneural gene atonal, can directly convert non-neural cells into neurons with the anterior features. In the mouse, ath3 expression initially occurs widely in the developing nervous system and then gradually becomes restricted to the neural retina. Here, we characterized the genomic organization and promoter activity of mouse ath3 (Math3). Math3 gene consists of two exons separated by an 8-kilobase intron, and the whole protein-coding region is located in the second exon. Transcription starts at two sites, which are 75 nucleotides apart from each other, and there is no typical TATA box in the upstream region of either start site. Transient transfection analysis showed that the 5'-region of Math3 can direct efficient expression in neuroblastoma cells but not in glioma or fibroblast cells. Deletion studies revealed that the proximal 193-base pair region, which contains the downstream transcription initiation site but not the upstream site, is essential for the Math3 promoter activity and can direct efficient expression in neuroblastoma cells. In contrast, retrovirus-mediated promoter analysis demonstrated that a region further upstream is additionally necessary for retinal expression. These results indicate that Math3 promoter contains two essential regulatory regions, the proximal 193-base pair region, which confers efficient neural-specific expression, and a region further upstream, required for retinal expression.
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PMID:Structure and promoter analysis of Math3 gene, a mouse homolog of Drosophila proneural gene atonal. Neural-specific expression by dual promoter elements. 949 61

Neuroblastoma is derived from the sympathetic nervous system and might arise as a result of impaired differentiation, retaining the neuroblastic tumor cells in the cell cycle. Thus, to understand the genesis of neuroblastoma, the study of mechanisms and genes regulating normal sympathetic development is of potential interest. The basic helix-loop-helix transcription factors human achaete-scute homolog-1 (HASH-1) and deciduum, heart, autonomic nervous system, and neural crest derivatives (dHAND) are expressed in the sympathetic nervous system of embryonic mice and chicken, with undetectable postnatal expression. By in situ hybridization technique, we show that dHAND was expressed by human sympathetic neuronal and extra-adrenal chromaffin cells throughout embryonic and fetal life, and was initially expressed in immature chromaffin cells of the adrenal gland. With overt chromaffin differentiation, dHAND was down-regulated. HASH-1, in contrast, was expressed in human sympathetic cells only at the earliest embryonic ages examined (Week 6.5 to 7). All examined neuroblastoma specimens (25/25) and all cell lines (5/5) had detectable dHAND mRNA levels. HASH-1 expression in tumor specimens was more restricted, although all cell lines (5/5) were HASH-1-positive. These results show that neuroblastoma tumors have retained embryonic features, suggesting that many neuroblastomas are blocked at an early stage of normal development when HASH-1 and dHAND are expressed. dHAND also appears to be a reliable and potentially useful clinical diagnostic marker for neuroblastoma, because expression was not dependent on tumor or differentiation stages and other pediatric tumors were dHAND-negative.
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PMID:The basic helix-loop-helix transcription factor dHAND, a marker gene for the developing human sympathetic nervous system, is expressed in both high- and low-stage neuroblastomas. 995 12


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