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)

The neuropeptides vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and substance P (SP) as well as insulin and insulin-like growth factor 1 (IGF-1) were labeled with biotin, fluorescent dyes, and radioactivity to characterize the expression of peptide receptor of a novel cancer cell line, established from a human glioblastoma multiforme. Thus, not only binding sites could be detected but advantages and disadvantages of the different labels could be compared, too. With all three markers, the presence or absence of the receptors could be answered rapidly and sensitively. The glioblastoma cells express receptors for VIP (IC(50) = 9 nM +/- 30%), insulin (K(d) = 0.66 nM +/- 14%, B(max) = 0.028 nM +/- 13%), and IGF-1 (K(d) = 21 nM +/- 25%, B(max) = 1.65 nM +/- 24%), but there are no binding sites for NPY and SP. As especially VIP and IGF-1 receptors are expressed in huge amounts, these receptors might be an interesting target for tumor diagnostics and therapy.
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PMID:Differently labeled peptide ligands for rapid investigation of receptor expression on a new human glioblastoma cell line. 1115 Jun 51

Glioblastomas rarely metastasize outside the CNS. We biologically characterized a case of secondary glioblastoma associated with extracranial progression and distant metastasis. A 42-year-old male patient was subjected to craniotomy for a left temporal tumor (astrocytoma grade II) and subsequently underwent another 3 craniotomies due to tumor recurrences. At the third craniotomy, extracranial progression was noted, and the tumor was classified as a glioblastoma. In order to pinpoint the genes expressed differentially in the intracranial primary tumor and the metastatic tumors, we used cDNA microarray. The patterns of gene expression in these 2 samples were highly similar, suggesting that the mechanism of metastasis was direct infiltration of tumor cells into extracranial blood vessels. Insulin-like growth factor binding protein-2 was overexpressed in both primary and metastatic tumors. Immunohistochemical studies of DNA-dependent protein kinase, which participates in the repair of DNA, was strongly positive in the samples obtained at the first and second operations, but the positive rates were markedly reduced in the specimens obtained at the third and fourth operations. These results suggest that insulin-like growth factor binding protein-2 and deficiency of DNA-dependent protein kinase proteins promoted tumor progression in the present case.
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PMID:Biologic characterization of a secondary glioblastoma with extracranial progression and systemic metastasis. 1262 29

Insulin-like growth factor-binding protein-3 (IGFBP-3) regulates IGF bioactivity and also independently modulates cell growth and survival. By using a yeast two-hybrid screen to identify IGFBP-3-interacting proteins, we cloned humanin (HN) as an IGFBP-3-binding partner. HN is a 24-aa peptide that has been shown to specifically inhibit neuronal cell death induced by familial Alzheimer's disease mutant genes and amyloid-beta (Abeta). The physical interaction of HN with IGFBP-3 was determined to be of high affinity and specificity and was confirmed by yeast mating, displaceable pull-down experiments with (His)-6-tagged HN, and ligand blot experiments. Co-immunoprecipitation of IGFBP-3 and HN from mouse testes confirmed the interaction in vivo. In cross-linking experiments, HN bound IGFBP-3 but did not compete with IGF-I-IGFBP-3 binding; competitive ligand dot blot experiments revealed the 18-aa heparin-binding domain of IGFBP-3 as the binding site for HN. Alanine scanning determined that F6A-HN mutant does not bind IGFBP-3. HN but not F6A-HN inhibited IGFBP-3-induced apoptosis in human glioblastoma-A172. In contrast, HN did not suppress IGFBP-3 response in SH-SY5Y neuroblastoma and mouse cortical primary neurons. In primary neurons, IGFBP-3 markedly potentiated HN rescue ability from Abeta1-43 toxicity. In summary, we have identified an interaction between the survival peptide HN and IGFBP-3 that is pleiotrophic in nature and is capable of both synergistic and antagonistic interaction. This interaction may prove to be important in neurological disease processes and could provide important targets for drug development.
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PMID:Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. 1456 95

Full activation of protein kinase B (PKB)/Akt requires phosphorylation on Thr-308 and Ser-473 by 3-phosphoinositide-dependent kinase-1 (PDK1) and Ser-473 kinase (S473K), respectively. Although PDK1 has been well characterized, the identification of the S473K remains controversial. A major PKB Ser-473 kinase activity was purified from the membrane fraction of HEK293 cells and found to be DNA-dependent protein kinase (DNA-PK). DNA-PK co-localized and associated with PKB at the plasma membrane. In vitro, DNA-PK phosphorylated PKB on Ser-473, resulting in a approximately 10-fold enhancement of PKB activity. Knockdown of DNA-PK by small interfering RNA inhibited Ser-473 phosphorylation induced by insulin and pervanadate. DNA-PK-deficient glioblastoma cells did not respond to insulin at the level of Ser-473 phosphorylation; this effect was restored by complementation with the human PRKDC gene. We conclude that DNA-PK is a long sought after kinase responsible for the Ser-473 phosphorylation step in the activation of PKB.
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PMID:Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. 1526 62

We examined whole genomic aberrations of biopsied samples from 19 independent glioblastomas by array-based comparative genomic hybridization analysis. The highest frequencies of copy number gains were observed on RFC2 (73.3%), EGFR (63.2%), and FGR, ELN, CDKN1C , FES, TOP2A, and ARSA (57.9% each). The highest frequencies of copy number losses were detected on TBR1 (52.6%), BMI1 (52.6%), EGR2 (47.4%), DMBT1 (47.4%), MTAP (42.1%), and FGFR2 (42.1%). The copy number gains of CDKN1C and INS and the copy number losses of TBR1 were significantly correlated with longer survival of patients. High-level amplifications were identified on EGFR, SAS/CDK4, PDGFRA, MDM2, and ARSA. These genes are assumed to be involved in tumorigenesis or progression of glioblastomas. The first attempts to apply detrended fluctuation analysis to copy number profiles by considering the reading direction as the time axis demonstrated that higher long-term fractal scaling exponents (alpha2) correlated well with longer survival of glioblastoma patients. The present study indicates that array-based comparative genomic hybridization analysis has great potential for assessment of copy number changes and altered chromosomal regions of brain tumors. Furthermore, we show that nonlinear analysis methods of whole genome copy number profiles may provide prognostic information about glioblastoma patients.
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PMID:Detrended fluctuation analysis of genome-wide copy number profiles of glioblastomas using array-based comparative genomic hybridization. 1549 95

Insulin-like growth factor binding proteins (IGFBPs) comprise a family of proteins that bind and regulate the functions of IGFs. One of the IGFBPs, IGFBP2, has recently been shown to be overexpressed in glioblastoma. Overexpression of IGFBP2 contributes to the invasiveness of glioblastoma and correlates with histologic grade and survival in patients with diffuse gliomas, suggesting that IGFBP2 expression may contribute to the glioma formation and/or progression. The expression of other IGFBP family members in gliomas has, however, not been examined in detail. This study was designed to evaluate the expression of IGFBP3 and IGFBP5 in diffuse gliomas using immunohistochemistry applied to a tissue array constructed from 259 gliomas, including ten gliosarcomas. Expression of IGFBP5 correlated significantly with glioma histologic grade. 83% (58/70) of glioblastomas (WHO Grade IV) were positive for IGFBP5, which was significantly higher than WHO Grade III gliomas (41%, 41/101) or WHO Grade II gliomas (18%, 13/72) (p<0.001). In contrast, IGFBP3 was expressed in 17%, 23%, and 17% of WHO Grade IV, Grade III, and Grade II gliomas, respectively (p>0.05). There was no significant difference in IGFBP3 expression among different grades of glioma. Our study thus demonstrates that the expression of IGFBP5, but not IGFBP3, increases with glioma anaplastic progression. The strong correlation between overexpression of IGFBP5 and histologic grade suggests that, in addition to IGFBP2, IGFBP5 may also play a role in glioma progression.
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PMID:Overexpression of IGFBP5, but not IGFBP3, correlates with the histologic grade of human diffuse glioma: a tissue microarray and immunohistochemical study. 1670 Jun 16

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) promotes apoptosis of cancer cells by both IGF-dependent and IGF-independent mechanisms. In vitro phosphorylation of IGFBP-3 by DNA-dependent protein kinase (DNA-PK) has been reported but with unknown functional relevance. Using a chemical inhibitor for DNA-PK in prostate cancer cells and a paired system of glioblastoma cell lines that either lack or express DNA-PK, we show that the apoptosis-promoting and growth-inhibitory actions of IGFBP-3 are completely abrogated in the absence of catalytically active DNA-PK. In the absence of DNA-PK activity, IGFBP-3 has reduced nuclear accumulation and is unable to bind its nuclear binding partner retinoid X receptor (RXR) alpha. We assessed the importance of the three potential DNA-PK phosphorylation sites in IGFBP-3 using PCR-based site-directed mutagenesis. When transfected into 22RV1 cells, IGFBP-3-S165A and IGFBP-3-T170A functioned in an identical manner to wild-type IGFBP-3 to induce apoptosis. In contrast, IGFBP-3-S156A was unable to promote apoptosis and exhibited reduced nuclear accumulation, suggesting a key role for DNA-PK-dependent phosphorylation in the regulation of IGFBP-3 action. These studies reveal a novel regulatory mechanism for the actions of IGFBP-3 in prostate cancer and show phosphorylation of Ser(156) to be functionally critical in its apoptosis-inducing actions.
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PMID:Phosphorylation by DNA-dependent protein kinase is critical for apoptosis induction by insulin-like growth factor binding protein-3. 1710 24

PTEN is an important tumor-suppressor gene associated with many cancers. Through expression profiling of glioblastoma tissue samples and prostate cancer xenografts, we identified a molecular signature for loss of the PTEN tumor suppressor in glioblastoma and prostate tumors. The PTEN signature consists of a minimum of nine genes, several of which are involved in various pathways already implicated in tumor formation. Among these signature genes, the most significant was an increase in insulin growth factor-binding protein 2 (IGFBP-2) mRNA. Up-regulation of IGFBP-2 was confirmed at the protein level by Western blot analysis and validated in samples not included in the microarray analysis. The link between IGFBP-2 and PTEN was of particular interest because elevated serum IGFBP-2 levels have been reported in patients with prostate and brain tumors. To further investigate this link, we determined that IGFBP-2 expression is negatively regulated by PTEN and positively regulated by phosphatidylinositol 3-kinase (PI3K) and Akt activation. In addition, Akt-driven transformation is impaired in IGFBP2(-/-) mouse embryo fibroblasts, implicating a functional role for IGFBP-2 in PTEN signaling. Collectively, these studies establish that PTEN and IGFBP-2 expression are inversely correlated in human brain and prostate cancers and implicate serum IGFBP-2 levels as a potential serum biomarker of PTEN status and PI3K Akt pathway activation in cancer patients.
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PMID:Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. 1737 10

Many studies support a role for insulin-like growth factors (IGFs) in the regulation of tumor cell biology. We hypothesized that single-nucleotide polymorphisms (SNPs) in IGF genes are risk factors for glioma and meningioma. To test the hypothesis, we examined associations of brain tumor risk with nine variants in five IGF genes in a hospital-based case-control study. The study was conducted at hospitals in Boston, Phoenix, and Pittsburgh between 1994 and 1998. Eligible cases were individuals (18 years or older) newly diagnosed with glioma or meningioma. Controls were selected among patients who were admitted to the same hospitals for a variety of nonmalignant conditions and frequency matched to cases by hospital, age, sex, race, and distance from residence. The present analysis was restricted to non-Hispanic whites. DNA was extracted from blood samples collected from 354 glioma cases, 133 meningioma cases, and 495 control individuals. We evaluated nine SNPs in five IGF genes (IGF1, IGF1R, IGF2, IGF2R, and IGFBP3). The majority of the analyzed IGF SNPs did not display statistically significant associations with glioma or meningioma. For glioma, one IGF1R SNP (rs2272037) indicated a possible association. No indications of association were seen for glioblastoma, but for low-grade gliomas, the odds ratio under a dominant model was 0.56 (95% confidence interval [CI], 0.35-0.90) for IGF1 rs6220, 2.98 (95% CI, 1.65-5.38) for IGF1R rs2272037, and 1.60 (95% CI, 0.90-2.83) for IGF1R rs2016347. Overall, our results do not provide strong evidence of associations of brain tumor risk with IGF polymorphic variants but identify several associations for glioma that warrant further examination in other, larger studies.
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PMID:Genetic variation in insulin-like growth factors and brain tumor risk. 1856 69

In this study, we investigated the protein expression of platelet-derived growth factor receptor (PDGFR), insulin like growth factor-1 receptor (IGF-1R), phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated kinase (ERK1/2) in five primary glioblastoma (GB), with a view to their possible use as therapeutic targets. Our results demonstrated that appreciable levels of these proteins could be detected in the analysed GB cell lines, except for a low level of PDGFR and ERK1/2 expression in one GB cell line. The small molecule inhibitors towards IGF-1R, PDGFR, PI3-K and ERK1/2 respectively, have only modest or no anti-tumour activity on GB cells and therefore their combination with other therapy modalities was analysed. The interaction between small inhibitors and radiation was mostly additive or sub-additive; synergistic interaction was found in five of forty analysed combinations. Our results showed that GB cells are in general resistant to treatment and illustrate the difficulties in predicting the treatment response in malignant gliomas.
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PMID:Growth factor receptors signaling in glioblastoma cells: therapeutic implications. 1904 76


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