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)

Many studies have established that a select subset of normal cellular genes are altered in cancer by point mutations, translocations or gene amplification. However, the vast majority of genetic changes that occur in neoplastic cells have not yet been identified. In an attempt to identify some of these other genetic changes, we have recently isolated a gene, GLI, by virtue of its amplification in a human glioblastoma. Subsequently, GLI was found to be amplified in other human glioblastomas (ref. 3 and unpublished data). To understand better the role of GLI in human neoplasia, we have now cloned the GLI complementary DNA (cDNA) and determined its nucleotide sequence. Analysis of the predicted translation product reveals that it contains five repeats of a DNA binding consensus sequence (zinc finger) originally described in Xenopus Transcription Factor III A (TFIIIA). Furthermore, these zinc fingers contain sequence elements that suggest the GLI gene product is a member of the recently described Kruppel family of zinc finger proteins. Additional experiments demonstrate that GLI is an evolutionarily conserved gene that is expressed in embryonal carcinoma cells but not in most adult tissues. The link between the developmentally important Kruppel family of genes and GLI is interesting considering the similarities between developing embryonic and neoplastic tissue.
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PMID:The GLI gene is a member of the Kruppel family of zinc finger proteins. 283 61

Biopsies and cell culture, respectively, of four human glioblastoma multiforme (WHO 4) have been evaluated for gene amplification using reverse chromosome painting. Three of the tumours showed amplified domains within chromosome bands 12q13-15. The exact localisation and extension of the amplified domains, however, varies within this region. Southern blot analysis revealed amplification of the GLI oncogene in two of the glioblastomas which were found to contain amplified domains within 12q13-15. Reverse chromosome painting also identified amplified domains within bands 7q21 and 9p23-24. Amplification within region 9p23-24 has previously not been reported in glioblastoma. The amplified domain encompassing 9p23-24 was detected in the same glioblastoma which contained an amplification unit within bands 12q13-14. These data, together with previous reports, indicate that amplifications are predominantly found on chromosomes 7, 9 and 12 in glioblastoma. In addition, this study provides further evidence that coamplification is not a rare event in glioblastoma.
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PMID:DNA amplifications on chromosomes 7, 9 and 12 in glioblastoma detected by reverse chromosome painting. 765 43

We have investigated 234 tumors of the central nervous system for amplification of 9 different loci from 12q13-14 and report that about 15% of the anaplastic astrocytomas and glioblastomas show amplification at this chromosomal region. The genes most frequently amplified were CDK4 and SAS (18 of 19 cases). MDM2 was coamplified with CDK4 and SAS in 11 tumors while one glioblastoma showed only MDM2 amplification. Some amplicons additionally included GADD153 (9 cases), GLI (6 cases), A2MR (3 cases), and the anonymous locus D12S8 (2 cases). Either MDM2 or CDK4 and SAS showed the highest amplification level in each individual amplicon and amplification of these genes was consistently accompanied by strong overexpression. Our results thus suggest CDK4, SAS, and MDM2 as main targets for the amplification; however, the possibility exists that all amplicons share a common amplified region between MDM2 and CDK4/SAS which might contain one or more as yet unidentified genes.
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PMID:Amplification of multiple genes from chromosomal region 12q13-14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM2. 804 75

The pair-rule gene, odd-paired (opa), is essential for parasegmental subdivision of the Drosophila embryo. In addition to its previously defined role in the activation of wingless (wg) in odd parasegments, we find that opa is required for the timely activation of wg in the remaining parasegments and for the timely activation of engrailed (en) in all parasegments. opa encodes a zinc finger protein with fingers homologous to those of the Drosophila segment polarity gene ciD, the human glioblastoma gene GLI and the Caenorhabditis elegans sex determination gene tra-1. Previous work showed that opa activity was essential for the establishment of alternate parasegments, suggesting opa expression or activity would be spatially restricted like other pair-rule genes. Instead, opa mRNA and protein are found throughout all segment primordia. Thus, opa does not act in a spatially restricted manner to establish the position of en and wg expression. Rather, opa must cooperate with other spatially restricted proteins to achieve proper subdivision of the Drosophila embryo.
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PMID:odd-paired: a zinc finger pair-rule protein required for the timely activation of engrailed and wingless in Drosophila embryos. 828 24

The most common types of brain tumors in adults are collectively known as gliomas. The most common glioma is the most malignant, the glioblastoma. Double minute chromosomes, known to represent amplified genes, are found in 50% of glioblastomas. Four genes have been identified as being amplified in more than single cases of glioblastomas; MYCN, GLI, PDGFRA and EGFR. The first three have been reported in a few per cent of malignant gliomas, and EGFR in around 40% of glioblastomas. The latter two genes code for growth factor receptors. On amplification, the genes for these receptors frequently become rearranged, resulting in changes in the regions of their transcripts that code for the extra-cellular domains of these proteins. Such aberrant proteins may provide us with cell-surface, tumor-specific, epitopes. These findings provide simple examples of the impact the use of modern molecular biological techniques will have for our understanding and treatment of tumors in the future.
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PMID:Amplified genes in human gliomas. 844 75

Gliomas represent the largest group of primary brain tumors in adults. The astrocytic variants are the most common and the adult forms are histologically stratified into three malignancy grades. Of these glioblastoma is the most common and the most malignant; it has also been best studied by molecular genetics and cytogenetics. Double-minute chromosomes, known to represent amplified genes, are found in 50% of glioblastomas. Amplified genes are not detected in the most benign of the astrocytomas. Many genes have been shown to be amplified in more than single cases of gliomas and these include EGFR, CDK4, SAS, MDM2, GLI, PDGFAR, MYC, N MYC, MYCL1, MET, GADD153, and KIT. The most commonly amplified genes in glioblastomas are EGFR (in approximately 40%), CDK4, and SAS (in approximately 15%). The remainder of the genes are amplified at lower frequency. The best mapped amplicon in gliomas involves the 12q13-14 region. The amplicon is of undetermined size, encompasses a number of genes, and may be rearranged. It occurs in 15% of glioblastomas and almost always includes the CDK4 and SAS genes, in about 10% of tumors the MDM2 gene, and at lower frequency GLI, GADD153, and A2MR. All but A2MR are overexpressed if amplified. The amplified EGFR gene is frequently rearranged, resulting in changes in the regions of the transcript that codes for the extracellular domain. The resultant receptor is constitutively activated. These findings provide examples of the impact the use of modern molecular biological techniques has had on our understanding of oncogenic mechanisms in gliomas.
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PMID:Gene amplification in human gliomas. 858 64

Gene amplification has been associated both with tumor stage and progression in human gliomas. Several distinct amplified loci have been identified by comparative genomic hybridization and Southern blot analysis. It has been increasingly recognized that amplified domains comprise multiple genes. Here, we demonstrate amplification of up to 12 different genes from an amplified domain at 12q13-15 that has been found in approximately 15% of astrocytomas and glioblastomas. The amplified genes were GLI, WNT1, MDM2, SAS, CDK4 OS-4, GAS16, GAS27, GAS41, GAS56, GAS 64 and GAS89. In one glioblastoma all 12 amplified genes were also found to be expressed. These results strongly warrant the search for as yet unidentified genes in regions previously reported to be amplified.
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PMID:Twelve amplified and expressed genes localized in a single domain in glioma. 888 87

We have reported previously that about 15% of anaplastic astrocytomas and glioblastomas show amplification and overexpression of one or more genes from chromosomal segment 12q13-q15 (G. Reifenberger et al., Cancer Res., 54, 4299-4303, 1994). The genes most frequently amplified and overexpressed were CDK4 (with coamplification of SAS) and MDM2. Because individual malignant gliomas showed CDK4/SAS amplification but no MDM2 amplification and vice versa, the possibility remained of a common amplification target gene located between CDK4 and MDM2. We have addressed this question by performing a detailed amplicon mapping of a series of 24 primary malignant gliomas and two glioblastoma cell lines with 12q13-q15 amplification. All tumors and cell lines were analyzed at eight gene loci and six anonymous loci from 12q13-q15, including seven loci located between CDK4 and MDM2. These studies revealed two centers of amplification, one at CDK4/SAS and the other at MDM2. A number of loci located close to either MDM2 or CDK4/SAS, including the genes GADD153, GLI, RAP1B, A2MR, and IFNG, were found to be coamplified in some tumors but not overexpressed consistently. All amplicons were discontinuous between CDK4/SAS and MDM2. Our results thus exclude a common amplification target between CDK4/SAS and MDM2 and provide additional evidence that these genes represent two independent targets of selection.
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PMID:Refined mapping of 12q13-q15 amplicons in human malignant gliomas suggests CDK4/SAS and MDM2 as independent amplification targets. 891 48

The GLI gene encodes a transcription factor harboring five zinc finger motifs that bind to DNA in a sequence-specific manner. The gene was originally identified because of its amplification in a human glioblastoma, and previous studies have shown it to be amplified in a significant proportion of mesenchymal tumors, such as childhood sarcomas. Here we evaluate GLI gene expression in bone and soft tissue sarcomas of adult patients. Samples from 40 patients (37 sarcomas and 3 benign mesenchymal tumors) and samples of 15 normal mesenchymal tissues were examined for GLI gene amplification and expression by Southern hybridization, reverse transcription-PCR of tissue RNA, and immunohistochemistry, using a new polyclonal GLI antibody developed against an epitope outside of the zinc finger region. In contrast to childhood sarcomas, amplification of the GLI gene was not observed in sarcomas of adult patients. Although GLI gene expression in sarcomas was significantly higher than that in normal mesenchymal tissues (P < 0.0001), the levels were very variable. Attempts to correlate the expression data with different pathophysiological parameters only showed a significant relationship to tumor grade. Based on these data, increased levels of GLI gene expression may be indicative of the aggressiveness of the tumor.
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PMID:GLI gene expression in bone and soft tissue sarcomas of adult patients correlates with tumor grade. 1021 97

The identification of brain tumor stem-like cells (BTSCs) has implicated a role of biological self-renewal mechanisms in clinical brain tumor initiation and propagation. The molecular mechanisms underlying the tumor-forming capacity of BTSCs, however, remain unknown. Here, we have generated molecular signatures of glioblastoma multiforme (GBM) using gene expression profiles of BTSCs and have identified both Sonic Hedgehog (SHH) signaling-dependent and -independent BTSCs and their respective glioblastoma surgical specimens. BTSC proliferation could be abrogated in a pathway-dependent fashion in vitro and in an intracranial tumor model in athymic mice. Both SHH-dependent and -independent brain tumor growth required phosphoinositide 3-kinase-mammalian target of rapamycin signaling. In human GBMs, the levels of SHH and PTCH1 expression were significantly higher in PTEN-expressing tumors than in PTEN-deficient tumors. In addition, we show that hyperactive SHH-GLI signaling in PTEN-coexpressing human GBM is associated with reduced survival time. Thus, distinct proliferation signaling dependence may underpin glioblastoma propagation by BTSCs. Modeling these BTSC proliferation mechanisms may provide a rationale for individualized glioblastoma treatment.
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PMID:Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. 1878 6


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