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)

The cyclin kinase inhibitor WAF1/CIP1, also termed CDKN1, mediates p53-induced cell cycle arrest in response to DNA damage. This property makes it an attractive tumour-suppressor candidate for a p53-associated tumour-suppressor gene. In order to investigate the role of WAF1/CIP1 in the pathogenesis of primary human brain tumours we performed single-stranded conformation polymorphism (SSCP) analysis and direct sequencing of exon 2 of the gene in a representative series of 158 brain tumours and corresponding blood samples. In addition, all tumours were examined for mutations in exons 5-8 of the p53 gene. Analysis of WAF1/CIP1 revealed multiple polymorphisms, the most abundant being AGC-->AGA (Ser-->Arg) at codon 31 with an allele frequency of 8.5%. Less common polymorphisms included GTG-->GGG (Val-->Gly) at codon 25, GCC-->ACC (Ala-->Thr) at codon 64, CGC-->CTC (Arg-->Leu) at codon 32, GGC-->AGC (Gly-->Ser) at codon 14 and GCG-->GTG (Ala-->Val) at codon 39 each with an allele frequency of 0.3%. These polymorphisms were all located in a conserved region of exon 2. Two of the polymorphisms were also seen in a group of 157 healthy controls indicating that WAF1/CIP1 polymorphisms do not predispose to cancer. None of the tumours included in our series showed a somatic mutation in WAF1/CIP1. All samples were also analysed for loss of heterozygosity on the short arm of chromosome 6 in the region of the WAF1/CIP1 locus. Allelic loss was observed in only one patient with a glioblastoma. Mutations in the p53 gene were found in 22 of 158 tumours. No association was found between any polymorphism of the WAF1/CIP1 gene, p53 mutations and histopathological tumour type. Our data indicate that WAF1/CIP1 mutations are probably not involved in the formation of primary human brain tumours.
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PMID:Multiple polymorphisms, but no mutations, in the WAF1/CIP1 gene in human brain tumours. 757 73

Water-soluble metabolites extracted from 20 astrocytic tumors (11 glioblastomas, 3 anaplastic astrocytomas, and 6 low-grade astrocytomas) and four normal brains were measured qualitatively and quantitatively using in vitro high-resolution proton magnetic resonance (1H-MR) spectroscopy. MR spectra from tumors exhibited characteristic patterns according to malignancy, presumably reflecting the metabolism of gliomas. Concentrations of choline-containing compounds, inositol, alanine, and glycine increased according to the malignancy, while that of total creatine decreased. In particular, glycine concentration was very high in glioblastoma, and an immunohistochemical study using anti-glycine antibody demonstrated that glycine was mainly distributed in glioma cells, not in proliferative endothelial cells. The ratios of choline-containing compounds and glycine to total creatine are useful parameters for grading gliomas, and the ratio of glycine to total creatine is useful for the differential diagnosis of glioblastoma from metastatic tumor. Such indications appearing in in vivo 1H-MR spectroscopy might provide clinically useful information on tumor metabolism and malignancy, and help assess the effects of radiation therapy and chemotherapy on gliomas.
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PMID:Proton magnetic resonance spectroscopy of astrocytic tumors: an in vitro study. 768 80

Wild-type p53 functions in the G1 DNA damage checkpoint pathway by activating gene transcription and preventing cell cycle progression. Others reported that mutation of the serine 386 codon in mouse p53 abolished its ability to suppress growth. Serine 386 of murine p53 and the homologous residue of human p53, serine 392, are phosphorylated in vivo and can be phosphorylated in vitro by casein kinase II (CKII). We constructed mutants that changed serine 392 of human p53 to alanine (p53-S392A) or aspartic acid (p53-S392D); cotransfection of both these mutants with a reporter gene carrying a p53-responsive element into the p53-null Saos-2 cell line activated transcription as well as did wild-type p53. Furthermore, both mutants blocked cell cycle progression after transient transfection in these cells. A stable derivative of the T98G human glioblastoma cell line was established that expressed p53-S392A in response to dexamethasone. Overexpression of this mutant activated transcription of the endogenous waf1 (also called cip1) and mdm2 genes to the same extent as wild-type p53 and also produced growth arrest. Finally, p53-S392A and p53-S392D suppressed foci formation by activated ras and adenovirus E1A oncogenes as efficiently as did wild-type p53. Thus, unlike mutants that altered the serine 15 phosphorylation site, elimination of the serine 392 phosphorylation site had no discernible effect on p53 function. We conclude that neither phosphorylation nor RNA attachment to serine 392 are required for human p53's ability to suppress cell growth or to activate transcription in vivo.
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PMID:The carboxy-terminal serine 392 phosphorylation site of human p53 is not required for wild-type activities. 793 49

C6 rat glioblastoma cells are able to attach to and to spread on culture dishes which are coated with purified central nervous system myelin, in contrast to normal astrocytes, fibroblasts or neurons which adhere poorly and are unable to spread on this substrate. The metalloprotease blockers o-phenanthroline and a newly developed oligopeptide could specifically inhibit C6 cell spreading on central nervous system myelin, suggesting a crucial role for a metalloprotease. Here we characterize this metalloproteolytic activity of C6 cells using a peptide degradation assay with the iodinated tetrapeptide carbobenzoxy-Phe-Ala-Phe-125I-Tyr-amide as a substrate. Purified, salt-washed C6 plasma membranes cleaved the peptide between alanine and phenylalanine, an effect which is strongly inhibited by o-phenanthroline, but not by thiol-blocking agents or aspartic and serine protease inhibitors. The metalloendoprotease is highly sensitive to phosphoramidon but insensitive to thiorphan. The enzyme is tightly bound to the plasma membrane but not G protein-phosphatidylinositol linked. It can be solubilized in part by the detergents 3-(3-cholamidopropyldimethylamino)-1-propanesulfonate or Triton X-114. Gel filtration chromatography using the Triton X-114-solubilized proteins or the proteins removed by a short trypsin treatment revealed a molecular weight range for the C6 enzyme of 60,000-100,000. Polymerase chain reaction with primers corresponding to endopeptidase 24.11 or to the highly conserved motif of the "astacin family" showed that both enzymes were not detectable in the C6 glioblastoma cells.
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PMID:Characterization of a membrane-bound metalloendoprotease of rat C6 glioblastoma cells. 803 33

Astrocytoma (WHO grade II, III), glioblastoma, malignant melanoma, and normal glial cell cultures, established from biopsies, were investigated by 1H MRS. At a 1H resonance frequency of 500 MHz (11.75 T) a high spectral resolution was achieved in 1D 1H spectra; in conjunction with 2D shift-correlated (COSY) MRS, resonances of alanine, aspartate, choline, creatine, glutamate, glutamine, hypotaurine, myo-inositol, phosphocreatine, phosphoryl-ethanolamine, phosphoryl-choline, lactate, lysine, N-acetylaspartate, taurine, threonine and valine could be identified. T1 relaxation times for the most prominent compounds are presented. T1 values of lactate ranged between 450 ms and 850 ms. The intensity of the lactate signal revealed differences between individual spectra, but exhibited no correlation between different tumor specimens or degree of malignancy. It was shown that the lactate signal at 1.3 ppm is covered by peaks arising from threonine and fatty acids. The choline signal level varied among spectra of different tumors, among tumors with similar degree of malignancy, and within the same tumor. Further preliminary differences due to aspartate, inositol and glutamine/glutamate were found in 1D and 2D COSY spectra between normal glial cells as well as different tumors. These results indicate that some differences observed in in vivo spectra may be attributable to secondary macroscopic structural changes (hypoxia, necrosis) and not to tumor inherent characteristics. Further correlation between in vivo and in vitro spectroscopy is therefore required.
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PMID:High-resolution one- and two-dimensional 1H MRS of human brain tumor and normal glial cells. 808 Jul 12

Cell culture techniques, high-resolution in vitro 1H NMR spectroscopy, and chromatographic analyses were used to compare the properties of three types of human brain and nervous system tumours. Cell lines were immunocytochemically characterized at all stages in culture with specific antibodies. Intracellular metabolites present in cell extracts were analysed by 1H NMR spectroscopy and by high performance liquid chromatography (HPLC). The spectra from meningiomas, neuroblastomas, and glioblastomas displayed, in addition to similarities-including the presence of signals from leucine, isoleucine, valine, threonine, lactate, acetate, glutamate, choline-containing compounds and glycine-certain distinguishing metabolic features. Spectra from meningiomas featured relatively high signals from alanine. Intense signals from creatine were present in neuroblastoma spectra, while in spectra from glioblastoma they were not detectable. We found statistically significant differences by 1H NMR spectroscopy in the amounts of alanine, glutamate, creatine, phosphorylcholine and threonine among the types of tumours examined. HPLC determinations confirmed that there were also other metabolites specific to a type of tumour, such as taurine, gamma-aminobutyric acid, and serine. We suggest that these findings have potential relevance for the development of non-invasive diagnosis of tumour lineage by 1H NMR spectroscopy in vivo.
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PMID:Characteristic metabolic profiles revealed by 1H NMR spectroscopy for three types of human brain and nervous system tumours. 873 81

Water-soluble metabolites extracted from 60 surgically excised samples of various brain tumors and four nontumorous lobectomized brains were measured quantitatively using in vitro high-resolution magnetic resonance spectroscopy. A detailed MR spectrum-histology correlation study in a glioblastoma was made, to reveal MR spectral changes in accordance with the density of glioma cells. Furthermore, three cases that had difficult preoperative diagnoses are discussed. MR spectra from gliomas exhibited characteristic patterns according to malignancy, presumably reflecting its metabolic effects. Concentrations of choline-containing compounds, inositol, alanine, glycine and phosphorylethanolamine (PEA) increased according to the degree of malignancy, but it was noteworthy that in glioblastoma the choline-containing compounds, inositol, alanine, glycine and phosphorylethanolamine increased according to the degree of malignancy. In particular, the glycine concentration was very high in glioblastoma. We also detected a large amount of taurine in medulloblastoma. Although the total creatine concentrations decreased according to the malignancy, the concentration of total creatine was relatively preserved in neuroectodermal tumors but was low in nonneuroectodermal tumors. N-acetyl-aspartate was unequivocally demonstrated in normal tissues, but could not be detected in nonneuroectodermal brain tumors such as metastatic brain tumor, meningioma, neurinoma and chordoma. In meningioma, although a high peak of choline-containing compounds has been reported uniquely by in vitro and in vivo 1H-MRS, we demonstrated that its concentration was not increased in meningioma; instead, there was an increased alanine content. 1H-MRS of neurinoma demonstrated high inositol peaks, and a large amount of inositol. The reason for the high inositol content in neurinoma is unknown, but the prominent peak of inositol on MR spectra should be useful for the differential diagnosis of neurinoma from meningioma. PEA concentration was increased four to five times in pituitary adenoma, malignant lymphoma, and medulloblastoma as compared with normal brain. Thus 1H-MRS might provide clinically useful information on tumor malignancy and characteristic tumor metabolism. Although excellent anatomical information of tumors can be readily obtained by magnetic resonance imaging. MRS provides metabolic information. MRS may provide additional information in cases in which the differential diagnosis of tumors by neuroimaging is difficult.
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PMID:Absolute concentrations of metabolites in human brain tumors using in vitro proton magnetic resonance spectroscopy. 925 Nov 9

Recently, there have been several reports describing the cloning and characterization of the novel family of protein tyrosine phosphatase-like receptor molecules (known as IA-2 and PTP-NP/PTP-IAR/IA-2beta/phogrin), which may act as autoantigens in diabetes. Here, we report the molecular characterization and chromosomal localization of a new isoform of this family in brain termed PTP-NP-2 (for PTP-NP tyrosine phosphatase isoform), and its function in rat primary hippocampal neurons. PTP-NP-2 has 48% identity to IA-2. The principal difference between PTP-NP-2 and PTP-NP is a 17-amino-acid insert near the N-terminus of PTP-NP that is absent in PTP-NP-2. Genomic DNA analysis indicates that the 17-amino-acid insert is coded by a separate exon, suggesting that both IA-2beta and PTP-NP-2 are isoforms arising by alternate splicing of the same gene. Reverse transcriptase-PCR revealed that both isoforms are present in human SH-SY5Y neuroblastoma cells. PTP-NP-2 mRNA expression is highly restricted, with a 5.5-kb specific transcript in human fetal and adult brain and 5.5 and 3. 8 kb in human adult pancreas. SH-SY5Y neuroblastoma and U87-MG glioblastoma cells showed specific transcripts of 5.5 and 3.8<HSP SP = "0.25">kb, respectively, indicating the existence of several isoforms of this molecule in the nervous system. The human gene encoding PTP-NP-2 was assigned to human chromosome 7q22-qter using Southern blot analysis of genomic DNAs from rodent/human somatic hybrid cell lines. Confocal microscopy analyses of rat primary hippocampal neurons revealed that PTP-NP-2 is abundantly expressed on synaptic boutons in primary neurons. Wild-type PTP-NP-2 showed no measurable tyrosine phosphatase activity using an in-vitro pNPP assay. Examination of the PTP-NP-2 catalytic consensus sequence revealed that this sequence differed from the typical tyrosine phosphatase-domain consensus sequence by an alanine to aspartate change (amino acid 930). Mutation of aspartate 930 to alanine produced a catalytically active enzyme, suggesting that native PTP-NP and its isoform PTP-NP-2 are catalytically inactive receptor protein tyrosine phosphatase homologues. Taken together, these results indicate that the tyrosine phosphatase PTP-NP-2 is a new isoform of PTP-NP tyrosine phosphatase, is expressed on synaptic boutons and may participate in the regulation of synaptic bouton endocytosis.
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PMID:Characterization and chromosomal localization of PTP-NP-2, a new isoform of protein tyrosine phosphatase-like receptor, expressed on synaptic boutons. 971 34

We have previously reported that heat stress induces expression of wild-type TP53 (formerly known as p53) activated factor 1 (CDKN1A, formerly known as WAF1) only when TP53 protein is wild-type using cells of a human glioblastoma cell line (A-172) and cells of its transformant (A-172/mp53/ 143) with a mutant TP53 (point mutation at codon 143 from Val to Ala) vector. Transfection of A-172 cells with the mutant TP53 vector abolished the heat-induced expression of CDKN1A, demonstrating the dominant negative nature of this TP53 mutant over the endogenous wild-type TP53. This kind of dominant negative TP53 mutant occurs frequently in various types of cancer. Overcoming this dominance or restoring the normal functions to these TP53 mutants is a new strategy for TP53-targeted cancer therapies. We examined whether glycerol can act as a chemical chaperone to correct the mutant TP53 conformation. No CDKN1A expression was induced after heating or treatment with glycerol at concentrations of 0.6 and 1.2 M in these transformants. In contrast, A-172/mp53/ 143 cells showed CDKN1A expression when they were heated in the presence of glycerol at 0.6 or 1.2 M, which was similar to the response of the parental and neo vector-transfected control cells. To test the generality of the effects of glycerol on mutant TP53, we used human osteosarcoma Saos-2 cells (lacking TP53) transfected with mutant TP53 and cells of two other human glioblastoma cell lines carrying mutant TP53. These cells showed similar CDKN1A expression when heated in the presence of glycerol at 0.6 or 1.2 M. These results suggest that glycerol is effective in restoring several TP53 mutants to normal TP53 function, leading to normal CDKN1A expression after heat stress. This observation provides a novel tool for correction of mutant TP53 conformation and may be applicable for TP53-targeted cancer therapy.
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PMID:Restoration of mutant TP53 to normal TP53 function by glycerol as a chemical chaperone. 1019 May 3

Chemotherapeutic agents and gamma-irradiation used in the treatment of brain tumors, the most common solid tumors of childhood, have been shown to act primarily by inducing apoptosis. Here, we report that activation of the CD95 pathway was involved in drug- and gamma-irradiation-induced apoptosis of medulloblastoma and glioblastoma cells. Upon treatment CD95 ligand (CD95-L) was induced that stimulated the CD95 pathway by crosslinking CD95 via an autocrine/paracrine loop. Blocking CD95-L/receptor interaction using F(ab')2 anti-CD95 antibody fragments strongly reduced apoptosis. Apoptosis depended on activation of caspases (interleukin 1beta-converting enzyme/Ced-3 like proteases) as it was almost completely abrograted by the broad range caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. Apoptosis was mediated by cleavage of the receptor proximal caspase FLICE/MACH (caspase-8) and the downstream caspase CPP32 (caspase-3, Apopain) resulting in cleavage of the prototype caspase substrate PARP. Moreover, CD95 was upregulated in wild-type p53 cells thereby increasing responsiveness towards CD95 triggering. Since activation of the CD95 system upon treatment was also found in primary medulloblastoma cells ex vivo, these findings may have implications to define chemosensitivity and to develop novel therapeutic strategies in the management of malignant brain tumors.
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PMID:Activation of the CD95 (APO-1/Fas) pathway in drug- and gamma-irradiation-induced apoptosis of brain tumor cells. 1020 87


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