Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta (TGF-beta), a regulator of cell growth and differentiation, is secreted by most cultured cells in latent form (L-TGF-beta). Activation of L-TGF-beta can be achieved by various physico-chemical treatments, including acidification, alkalinization, heating and chaotropic agents. Proposed physiological activators include proteinases and glycosidases, which, however, only lead to limited activation (15-20% of the total TGF-beta activity after acidic activation). In the present study L-TGF-beta 1 partially purified from human platelets was not activated by treatment with neuraminidase or the proteinases plasmin, endoproteinase Arg-C, elastase and chymotrypsin. The mechanism of activation of L-TGF-beta was further assessed by using the human glioblastoma cell line 308, which releases biologically active TGF-beta 2. Factor(s) secreted by 308 glioblastoma cells were found to be able to activate partially purified L-TGF-beta 1 from human platelets. Our finding may prove to constitute a physiologically relevant mechanism for the activation of latent forms of TGF-beta in vivo.
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PMID:Activation of human platelet-derived latent transforming growth factor-beta 1 by human glioblastoma cells. Comparison with proteolytic and glycosidic enzymes. 183 Feb 5

Protease nexin-II (PN-II) is a protease inhibitor that forms SDS-resistant inhibitory complexes with the epidermal growth factor (EGF)-binding protein, the gamma-subunit of nerve growth factor, and trypsin. The properties of PN-II indicate that it has a role in the regulation of certain proteases in the extracellular environment. Here we describe more of the amino-acid sequence of PN-II and its identity to the deduced sequence of the amyloid beta-protein precursor (APP). Amyloid beta-protein is present in neuritic plaques and cerebrovascular deposits in individuals with Alzheimer's disease and Down's syndrome. A monoclonal antibody against PN-II (designated mAbP2-1) recognized PN-II in immunoblots of serum-free culture medium from human glioblastoma cells and neuroblastoma cells, as well as in homogenates of normal and Alzheimer's disease brains. In addition, mAbP2-1 stained neuritic plaques in Alzheimer's disease brain. PN-II was a potent inhibitor of chymotrypsin with an inhibition constant Ki of 6 x 10(-10)M. Together, these data demonstrate that PN-II and APP are probably the same protein. The regulation of extracellular proteolysis by PN-II and the deposition of at least parts of the molecule in senile plaques is consistent with previous reports that implicate altered proteolysis in the pathogenesis of Alzheimer's disease.
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PMID:Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor. 250 28

The clinical and immunohistochemical features of supratentorial (5 patients) and cerebellar (1 patient) glioblastomas, in which giant cells were conspicuous were examined. Three of the patients died within 26 months after the first treatment, and the follow-up period is presently 1 year or less in the remaining patients. The giant cells either showed large and bizarre nuclei or were multinucleated. Both giant and smaller cells excluding neuronal, endothelial and infiltrative cells were positive for GFAP, vimentin, and alpha-1 anti-chymotrypsin. The strong positivity for PCNA staining indicated that the capacity of the giant cells to synthesis DNA was preserved. DNA fragmentation, measured by the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine-5'-triphosphate (dUTP)-biotin nick end labeling method, was observed in only 1 patient, who had received radiotherapy just before biopsy, and none of the patients showed bcl-2 positivity. Mutant type of p53 tumor suppressor gene was observed in the giant cells of 3 patients. Giant cell in glioblastoma is of glial origin, synthesizes DNA, and its progression may be related to tumor suppressor gene.
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PMID:Immunohistochemical study of giant cell in glioblastoma. 760 97

Protease inhibitors regulate a variety of physiological and pathological processes including angiogenesis, embryo implantation, intravascular fibrinolysis, wound healing, and tumor invasion. Tissue factor pathway inhibitor (TFPI) 2 is a Mr 32,000 Kunitz-type serine protease inhibitor that inhibits plasmin, trypsin, chymotrypsin, cathepsin G, and plasma kallikrein but not urokinase-type plasminogen activator, tissue plasminogen activator, or thrombin. In this study, we determined the relative amounts of TFPI-2 in low-, intermediate-, and high-grade human glioma cell lines and tumor tissue samples. TFPI-2 protein and mRNA levels (measured by Western and Northern blotting) were highest in low-grade glioma cells (Hs683), lower in anaplastic astrocytoma cells (SW1088 and SW1783), and undetectable in high-grade glioma cells (SNB19). Analysis of TFPI-2 protein in human normal brain and in glioma tumor tissues for TFPI-2 revealed the highest levels in normal brain, lesser amounts in low-grade gliomas and anaplastic astrocytomas, and undetectable amounts in glioblastomas. In situ hybridization of TFPI-2 mRNA with normal brain tissues revealed the greatest positivity in neurons, with moderate positivity in both glial and endothelial cells and moderate, little, or no TFPI-2 mRNA in low-grade glioma, anaplastic astrocytoma, and glioblastoma tumor tissue samples, respectively. We also found that recombinant TFPI-2 inhibited the invasiveness of SNB19 glioblastoma cells in a Matrigel assay in a dose-dependent manner. Collectively, these results suggest that TFPI-2 has a regulatory role in the invasiveness of gliomas in vitro and in vivo.
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PMID:Expression of tissue factor pathway inhibitor 2 inversely correlates during the progression of human gliomas. 1129 50

Human type-2 tissue factor pathway inhibitor (TFPI-2), also known as placental protein 5, is a 32 kDa serine proteinase inhibitor consisting of three tandemly arranged Kunitz-type inhibitor domains homologous to tissue factor pathway inhibitor. TFPI-2 strongly inhibits a wide variety of serine proteinases including trypsin, chymotrypsin, plasmin, kallikrein and blood coagulation factor XIa. In this study, we have isolated and characterized a genomic clone from an artificial chromosome genomic library that encodes the entire human TFPI-2 gene. The human TFPI-2 gene spans approximately 7 kb and consists of five exons and four introns. Each Kunitz-type domain is encoded by a single exon, similar to that observed for murine TFPI-2 and other Kunitz-type proteinase inhibitors. A total of 535 bp of the 3'-flanking region contain two probable polyadenylation sites (AATAAA) at +4297 and +4314. A single transcription initiation site was identified by oligo-capping and reverse transcription-PCR analysis. Transient transfection of reporter plasmids containing segments of the 5'-flanking region into human transformed bone marrow endothelial cells and glioblastoma cells identified an 85 bp region (-224 to -139) sufficient for transcription of the human TFPI-2 gene.
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PMID:Genomic structure and promoter activity of the human tissue factor pathway inhibitor-2 gene. 1134 22

Phenoxazines have shown diverse biological activities, but tumor-specific cytotoxic activity has not been investigated. A total of 24 phenoxazine derivatives (WM1-24) was investigated for their relative cytotoxicity against human tumor cell lines vs. normal cells. WM7 and WM8 showed the highest tumor-specificity index of 4.3 and 4.8, respectively. Considerable difference in drug-sensitivity was found among these tumor cell lines. Human promyelocytic leukemia HL-60 cells showed the highest sensitivity to both WM7 and WM8, followed by human oral squamous cell carcinoma (HSC-2, HSC-3, HSC-4), and human gingival fibroblast (HGF), pulp cell (HPC) and periodontal ligament fibroblast (HPLF) were the most resistant. WM7 and WM8 induced little or no internucleosomal DNA fragmentation, and activated caspase-3 in HSC-2, HSC-4 and human glioblastoma T98G cells. These compounds failed to induce autophagic cell death, as judged by acridine orange and microtubule-associated protein 1 light chain 3 (LC3)-GFP assays. These results suggested that the higher cytotoxicity of WM7 and WM8 are derived from the positively-charged quaternary nitrogen substituents on the phenoxazine ring and the electron density of nitrogen at N12, and that inhibition of autophagy is not always coupled with apoptosis induction.
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PMID:Tumor-specificity and type of cell death induced by phenoxazines. 1822 95

Toxic cyanobacterial blooms are a rich source of metabolites having a variety of biological activities. Two main groups of cyclic peptides, depsipeptides and ureido linkage-containing peptides, reportedly inhibit serine peptidases. We characterised their inhibitory properties against selected peptidases and investigated their influence on cell viability. The depsipeptide planktopeptin BL1125 is a strong linear competitive tight-binding inhibitor of leukocyte (K(i)=2.9 nm) and pancreatic (K(i)=7.2 nm) elastase and also of chymotrypsin (K(i)=6.1 nm). Anabaenopeptins B and F show no inhibition against chymotrypsin, but inhibit both elastases. The tested cyclic peptides do not inhibit trypsin, urokinase, kallikrein 1 or cysteine peptidases. All three tested cyanopeptides show no short-term cytotoxicity in concentrations of up to 10 mum, but impair the metabolic activity of normal human astrocytes after prolonged exposure (48-96 h), whereas glioblastoma cells, tumour cells of the same type, are resistant. Strong inhibition and relative selectivity of the tested cyanopeptides suggests that they are potential candidates for application in inflammatory diseases and possibly some types of cancers.
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PMID:Cytotoxic and peptidase inhibitory activities of selected non-hepatotoxic cyclic peptides from cyanobacteria. 1871 22

The Ptdlns-3-kinase (PI3-K) signaling pathway plays a vital role in cell survival, proliferation, apoptosis and differentiation in normal cells, as well as in diseases such as cancer and diabetes. Quantification of phospho-Akt is a standard way of assessing the activity of the PI3-K signaling pathway in both cells and tumors. This measurement is traditionally performed semiquantitatively using immunoassays such as Western blot. Here we report an LC-MS method to accurately measure the stoichiometry of Akt phosphorylation in biological samples. The procedure includes immunoprecipitation, gel electrophoresis, in-gel digestion, addition of isotopicaly labeled internal standards and LC-MS/MS. Two proteolytic enzymes, chymotrypsin and trypsin, were used to generate suitable peptide fragments for measuring Thr308 and Ser473 phosphorylation, respectively. The interday imprecision was estimated to be 3.8% and 2.3% for Thr308 and Ser473, respectively. This method has been tested on human T-cells grown in presence and absence of pervanadate and with or without a PI3-K inhibitor and on human glioblastoma cells (U-87 MG) grown in presence and absence of wortmannin (PI3-K inhibitor).The results of T cells suggest that the levels of Akt phosphorylation in untreated cells were below 1% for both phosphorylation sites. Pervanadate treatment provoked an 18-fold increase in phosphorylation of Thr308 and the PI3-K inhibitor partially reversed the increase. A comparison between LC-MS/MS and Western blotting suggests that the LC-MS based method is of comparable sensitivity and provides a more accurate phosphorylation stoichiometry, a wider dynamic range and more in-depth information. The application of the new method and its utility to providing predictive markers of response to targeted therapies is discussed.
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PMID:Stoichiometric quantification of Akt phosphorylation using LC-MS/MS. 1990 31