Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human neural-crest-derived tumor cell lines, including three neuroblastomas, an astrocytoma, a glioblastoma, a rhabdomyosarcoma and a melanoma were screened for the expression of the integrin alpha 4 beta 1 (VLA-4). The neuroblastomas IMR-32 and SK-N-SH, the astrocytoma 131-INI, the glioblastoma Fogerty and the rhabdomyosarcoma TE-671 expressed alpha 4 beta 1 as determined by cytofluorometry and immunoprecipitation. Another neuroblastoma line, LA-N-1, did not express alpha 4 beta 1. Analysis of immunoprecipitated alpha 4 beta 1 showed that the alpha 4 subunit from the various cell types differed in relative molecular weight (M(r)). The variability in the observed M(r) could be accounted for by differences in the levels of N-linked glycosylation. The observed variability in M(r) did not appear to affect function since intact cells and solubilized alpha 4 beta 1 bound to a synthetic peptide identical in sequence to the CS-1 region of the alternatively spliced IIICS domain of fibronectin, a known alpha 4 beta 1 ligand.
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PMID:Expression and ligand-binding function of the integrin alpha 4 beta 1 (VLA-4) on neural-crest-derived tumor cell lines. 153 75

The primary transcript of the calcitonin (CT)/calcitonin gene-related peptide (CGRP) is alternatively spliced in a cell-specific fashion to produce CT in thyroid C cells and CGRP in neuronal cells. The key step in this regulatory process is the recognition and inclusion of exon 4 to produce CT mRNA or nonrecognition and exclusion of exon 4 to produce CGRP mRNA. To determine whether inclusion/exclusion of CT exon is regulated independently of its position, we created a series of minigene constructs containing decreasing amounts of CT gene sequence. A human glioblastoma cell line, T98G, was tested and used as a CT exon exclusion cell line, while HeLa cells were used as a CT exon inclusion cell line. CT exon inclusion/exclusion was regulated when either the relative position of exon 4 within the CT gene was changed or when the exon with flanking sequence was inserted into a completely heterologous gene. Our results demonstrate that CT exon functions as a unit in a position-independent fashion in regulating its own inclusion/exclusion. We believe that the heterologous fusion gene containing only exon 4 and part of its flanking intron sequences will be useful for further defining the sequence elements involved in the regulation of CT/CGRP splicing.
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PMID:The calcitonin exon and its flanking intronic sequences are sufficient for the regulation of human calcitonin/calcitonin gene-related peptide alternative RNA splicing. 753 92

Transcripts for cysteine protease cathepsin B (CTSB) were found to be highly variable in the 5'-UTR (untranslated region). In cDNA clones from a human gastric adenocarcinoma cDNA library, we have identified two new exons (designated 2a and 2b) between exons 2 and 3 in the 5'-UTR of the gene. All of the exons of the 5'-UTR could be alternatively spliced to produce several transcript species. In addition, transcription was initiated from more than one promoter region. Using RT-PCR (reverse transcription-polymerase chain reaction) and primer extension assays, CTSB mRNA species were found to differ among tissues and between a glioblastoma sample and a cell line derived from it. Exons 2a and 2b were detected more frequently in tumor samples than in matched normal samples. Thus, factors related to the cell differentiation and environment seem likely to determine the types of transcripts that are expressed which in turn could influence the overall steady-state level of CTSB mRNAs and their rate of translation. Interestingly, at least three upstream translation initiation codons were observed and could constitute a means of controlling translation initiation.
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PMID:Identification of two new exons and multiple transcription start points in the 5'-untranslated region of the human cathepsin-B-encoding gene. 762 42

We have isolated four cDNA clones coding for human acidic fibroblast growth factor (aFGF) containing alternative 5' untranslated exons. Using RNAase protection analyses, we demonstrated the presence of at least four upstream, untranslated exons that are alternatively spliced to the first protein-coding exon. We designate these four untranslated exons, -1A, -1B, -1C and -1D. Splicing of these exons to the first coding exon will generate mRNA 1.A, 1.B, 1.C and 1.D respectively. Expression of these transcripts is regulated in a tissue-specific manner, as the major aFGF transcript in human brain frontal cortex differs from that in kidney. Furthermore, the pattern of aFGF transcripts in several glioblastoma cell lines tested is different from that in normal brain tissue. We isolated nine overlapping genomic clones containing these four upstream, untranslated exons. These four exons were localized on these clones by Southern hybridization and nucleotide sequence analysis. The overlapping clones are shown to be contiguous with our previously isolated genomic clones that contain the three aFGF-coding exons. The sizes of the four introns are 82.9, 71.1, 29.3 and 6.9 kbp. The transcriptional start sites of the two most upstream exons (-1A and -1B) have been mapped using RNAase protection and primer extension analyses. The sequences upstream of the start sites for aFGF 1.B mRNA do not contain a consensus TATA box. In contrast, the canonical CCAAT and TATA sequences are located at the proper distances from the transcription start site of aFGF 1.A mRNA.
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PMID:Gene structure and differential expression of acidic fibroblast growth factor mRNA: identification and distribution of four different transcripts. 767 25

Sequence analysis of two human tenascin encoding cDNA clones from a cDNA library of the U251 glioblastoma cell line revealed the presence of a novel 276 bp tenascin type III fibronectin like repeat. This alternatively spliced type III repeat designated AD1 is located between the previously identified repeats 10 and 11 and has sequence homology with human, chicken and mouse tenascin type III repeats. These results show that tenascin has at least 16 consecutive fibronectin like type III repeats. PCR amplification of random primed mRNA with specific type III repeat primers revealed a pattern of multiple alternative splices of AD1 and flanking type III repeats. The alternative splice variants were confirmed by direct sequencing. Differences were observed in the expression of the various alternative splices of tenascin mRNA between tumor and normal cells and may thus indicate differences in tenascin isoform expression and function in normal and tumor cells. PCR and Southern analysis of genomic DNA indicate that AD1 is coded by a single exon present in both human and mouse genome.
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PMID:A novel tenascin type III repeat is part of a complex of tenascin mRNA alternative splices. 768 Jan 13

Expression of alternatively spliced human FGF-1 (or aFGF) transcripts is regulated in a tissue-specific manner via multiple promoters. To identify the cis-regulatory elements in the brain-specific FGF-1.B promoter, we constructed a series of promoter deletions fused to the luciferase reporter gene and transfected into an FGF-1.B positive glioblastoma cell line, U1240MG, and a 1.B negative cell line, U1242MG. Results of transient transfections indicate three elements that are involved in the positive regulation of FGF-1.B expression. The core promoter is located in a 40-base pair region (between -92 and -49), and two regulatory regions (RR-1 and RR-2) are located within the 540-base pair region 5' to the major transcription start site (defined as +1). Electrophoretic mobility shift assays and footprinting analysis have identified sequence-specific binding sites in RR-1 and RR-2. Mutants of RR-2 abolished binding to nuclear proteins and showed diminished luciferase reporter activity. The effects seen are specific for the U1240MG cell line, supporting a role for RR-2 in the tissue-specific regulation of FGF-1.B. Southwestern analysis using an oligonucleotide probe derived from RR-2 (nucleotides -489 to -467) further identified a 37-kDa protein that is present in nuclear extracts from U1240MG and brain but not from U1242MG.
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PMID:Functional characterization of the brain-specific FGF-1 promoter, FGF-1.B. 771 33

DCC (deleted in colorectal cancer), a candidate tumor suppressor gene located in chromosome band 18q21.2, encodes a transmembrane protein of 1447 amino acids. Neogenin, a protein with nearly 50% amino acid identity to DCC, was recently identified because of its dynamic expression in the developing nervous system and gastrointestinal tract of the chicken. To explore a role for the human neogenin (NGN) gene in cancer, we have isolated cDNAs for two alternatively spliced forms of NGN, encoding proteins of 1461 and 1408 amino acids. Fluorescence in situ hybridization studies (FISH) localized NGN in chromosome band 15q22, a region infrequently affected by alterations in cancer. NGN transcripts of about 7.5 and 5.5 kb were detected in all adult tissues studied. In contrast to the frequent loss of DCC expression, no alterations in NGN expression were observed in more than 50 cancers studied, including glioblastoma, medulloblastoma, neuroblastoma, colorectal, breast, cervical and pancreatic cancer cell lines and xenografts. Based on their sequence conservation and similar expression during development, DCC and NGN may have related functions. However, the chromosomal location and ubiquitous expression of NGN in various human tumors suggest it is infrequently altered in cancer.
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PMID:Identification and characterization of neogenin, a DCC-related gene. 912 61

Using the technique of differential display-polymerase chain reaction (DD-PCR), we isolated a cDNA fragment that is over-expressed in glioblastoma multiforme tissue as compared to normal brain tissue. Sequence analysis indicated that this sequence is identical to the previously isolated human neuron-glia-related cell adhesion molecule hNr-CAM. Gene-specific RT-PCR analysis indicated that hNr-CAM is over-expressed in high-grade astrocytomas, gliomas and glioblastoma tumor tissues as compared to normal brain tissue. High levels of hNr-CAM expression also were observed in cell lines derived from astrocytomas, gliomas and glioblastoma multiforme tumors. Low levels of hNr-CAM expression were observed in neuroblastoma, meningiomas, melanoma, normal breast and prostate tumor tissues. Northern blot analysis showed an alternatively spliced mRNA of 1.4 kb in several tumors as compared to the 7.5 kb transcript found in normal brain tissue. Genomic Southern blot analysis of DNA from 3 brain tumor cell lines showed that over-expression of hNr-CAM in brain tumors was not due to gene amplification. In situ hybridization analysis indicated that 11 of the 20 human brain tumor samples studied showed hNr-CAM over-expression. Our results suggest that hNr-CAM is over-expressed in malignant brain tumors and can serve as a novel marker for brain tumor detection and perhaps therapy.
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PMID:Cell adhesion molecule Nr-CAM is over-expressed in human brain tumors. 959 Jan 16

Astrocytes exhibit significant changes in fibroblast growth factor receptor (FGFR) gene expression during malignant progression. These changes include induction of FGFR1 and concomitant loss of FGFR2 expression. The induction of FGFR1 is believed to endow malignant astrocytes with a selective growth advantage. Glioblastoma (the most malignant form of astrocytoma) cell lines, which exhibit the same pattern of FGFR gene expression as glioblastoma biopsies, were used to evaluate the contribution of FGFR1 expression to glioblastoma cell growth. Addition of phosphorothioate-modified antisense oligonucleotides complementary to the initiation site or the alpha exon of the FGFR1 gene suppressed growth of human glioblastoma-derived cell lines. Reverse antisense controls or antisense oligonucleotide complementary to FGFR2 had no effect on proliferation. Consistent with its growth-suppressive effect, FGFR1 antisense oligonucleotides markedly reduced expression of both FGFR1 mRNA and high-affinity bFGF binding sites, whereas FGFR1 reverse antisense control oligonucleotide had no effect. Antisense oligonucleotide targeted to the alpha exon of the FGFR1 gene suppressed alpha and beta alternatively spliced FGFR1 mRNA isoforms but did not alter the expression of related FGFR family members. Fluorescein-labeled antisense and reverse control oligonucleotides demonstrated cellular uptake and nuclear accumulation. These results indicate that alterations in FGFR expression may contribute to malignant proliferation in human astrocytomas. These findings also illustrate the high degree of selectivity that can be obtained with antisense oligonucleotides, a property that is essential for employing these reagents therapeutically.
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PMID:Suppression of glioblastoma cell growth following antisense oligonucleotide-mediated inhibition of fibroblast growth factor receptor expression. 1049 24

Voltage-gated K(+) channels (Kv1) are important in glia, being required for cell proliferation. Herein, reactive astrocytes from a rat cerebellar lesion were shown to contain Kv1.1, -1.2, -1.3, -1.4, and -1.6 alpha plus beta1.1 subunits, as well as an unusual beta2.1 constituent; the latter was also found in a glioblastoma C6 cell line, together with Kv1.1, -1.3, and -1.6 and beta1.1 subunits. Reverse transcriptase-polymerase chain reaction revealed a novel product of the beta2 gene in C6 cells and reactive astrocytes, but not in cultured astrocytes or rat normal brain. Its cloning identified a variant, Kvbeta2.1A, alternatively spliced between I24 and Y39. Despite this 14 residue deletion, Kvbeta2.1A assembled cotranslationally with Kv1.1 or -1.2 and, when coexpressed with Kv1. 4 in oocytes, increased the inactivation rate of this K(+) current. Whereas the full-length beta2.1 gave a large increase in the amplitude of the Kv1.1 current in oocytes, the effect of beta2.1A varied from a modest elevation of the current to a slight suppression in some cases. In summary, this is the first report of the existence of an alternatively spliced product of the Kvbeta2.1 gene in C6 cells and reactive astrocytes, and supports the involvement of its core region (residues 39 onward) in assembly with alpha subunits while excluding a contribution of the adjacent 14 residues to accelerating the inactivation of Kv1.4.
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PMID:A functional spliced-variant of beta 2 subunit of Kv1 channels in C6 glioma cells and reactive astrocytes from rat lesioned cerebellum. 1060 34


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