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:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human securin, pituitary tumor transforming gene (PTTG), is a protooncogene. Here we report expressions of PTTG and its interacting protein, PTTG-binding factor in human astrocytic cells. PTTG expression was higher in malignant cells than in primary astrocytes, whereas PTTG-binding factor was not. Using a xenotransplantable, glioma cell line (U87), we observed that knocking down PTTG mRNA by RNA silencing inhibited serum-induced proliferation by approximately 50%. Furthermore, in U87 cells PTTG expression was up-regulated by promalignant ligands epithelial growth factor (EGF) and TGFalpha, both at the protein and mRNA levels. PTTG induction by EGF receptor (EGFR) ligands could be blocked by the specific EGFR inhibitor, AG1478. Hepatocyte growth factor (HGF) also induced PTTG but to a lesser extent than EGF. Although EGF stimulates HGF secretion in U87 cells, the effect of EGF on PTTG mRNA expression is independent of HGF as neutralizing antibody against HGF failed to abolish EGF-induced up-regulation of PTTG mRNA. PTTG mRNA was unchanged by incubating U87 cells with the promalignant growth factor TGFbeta, apoptosis inducing TNFalpha and ligands for nuclear receptors, such as retinoic acid and retinoid X receptors and peroxisome proliferator-activated receptor-gamma, known for their growth-inhibitory and apoptosis-inducing effects on gliomas. In addition, 17beta-estradiol and Ca2+, known to activate PTTG expression, did not change PTTG mRNA levels in U87 cells. In summary, we show higher PTTG expression in astrocytoma than normal astrocytes and secondly, PTTG is involved in glioma cell growth. Finally, regulation of its expression has glioma-specific features and is selectively regulated by promalignant cytokines including EGFR ligands and HGF.
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PMID:Expression of pituitary tumor transforming gene (PTTG) and its binding protein in human astrocytes and astrocytoma cells: function and regulation of PTTG in U87 astrocytoma cells. 1517 45

Arsenic trioxide (As(2)O(3)) has shown considerable efficacy in treating hematological malignancies with induction of programmed cell death (PCD) type I, apoptosis. However, the mechanisms underlying the antitumor effect of As(2)O(3) on solid tumors are poorly defined. Previously, we reported that As(2)O(3) induced autophagic cell death (PCD type II) but not apoptosis in human malignant glioma cell lines. The purpose of this study was to elucidate the molecular pathway leading to autophagic cell death. In this study, we demonstrated that the cell death was accompanied by involvement of autophagy-specific marker, microtubule-associated protein light chain 3 (LC3), and damage of mitochondrial membrane integrity, but not by caspase activation. Analysis by cDNA microarray, RT-PCR, and Western blot showed that cell death members of Bcl-2 family, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) and its homologue BNIP3-like (BNIP3L), were upregulated in As(2)O(3)-induced autophagic cell death. Exogenous expression of BNIP3, but not BNIP3L, induced autophagic cell death in malignant glioma cells without As(2)O(3) treatment. When upregulation of BNIP3 induced by As(2)O(3) was suppressed by a dominant-negative effect of the transmembrane-deleted BNIP3 (BNIP3 Delta TM), autophagic cell death was inhibited. In contrast, BNIP3 transfection augmented As(2)O(3)-induced autophagic cell death. These results suggest that BNIP3 plays a central role in As(2)O(3)-induced autophagic cell death in malignant glioma cells. This study adds a new concept to characterize the pathways by which As(2)O(3) acts to induce autophagic cell death in malignant glioma cells.
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PMID:Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. 1559 27

The myelodysplasia/myeloid leukemia factor 1-interacting protein MLF1IP is a novel gene which encodes for a putative transcriptional repressor. It is localized to human chromosome 4q35.1 and is expressed in both the nuclei and cytoplasm of cells. Northern and Western blot analyses have revealed MLF1IP to be present at very low amounts in normal brain tissues, whereas a number of human and rat glioblastoma (GBM) cell lines demonstrated a high level expression of the MLF1IP protein. Immunohistochemical analysis of rat F98 and C6 GBM tumor models showed that MLF1IP was highly expressed in the tumor core where it was co-localized with MLF1 and nestin. Moreover, MLF1IP expression was elevated in the contralateral brain where no tumor cells were detected. These observations, together with previous data demonstrating a role for MLF1IP in erythroleukemias, suggest a possible function for this protein in glioma pathogenesis and potentially in other types of malignancies.
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PMID:Regulation of myeloid leukemia factor-1 interacting protein (MLF1IP) expression in glioblastoma. 1589 39

A key regulatory mechanism in cell motility is the control of myosin activity, which in non-muscle cells is determined by phosphorylation of the myosin regulatory light chain (MRLC). Here we show that MRLC-interacting protein (MIR)-interacting saposin-like protein (MSAP) enhances cell spreading in fibroblasts and migration of rat C6 glioma cells through increases in MRLC phosphorylation. Overexpression of MSAP enhanced the motility of glioma cells measured in matrigel invasion chambers and using a scratch assay. Downregulation of MSAP by RNA interference significantly decreased glioma cell migration and phosphorylation of MRLC. Inhibition of the corresponding MRLC kinase by ML-7 did not affect migration of MSAP-overexpressing cells. The present results show that MSAP controls glioma cell migration via enhancement of MRLC phosphorylation. This effect is independent of the activity of MRLC kinase. Thus, MSAP is a novel modulator of cell motility that influences migration of glioma cells and possibly other tumors.
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PMID:MSAP enhances migration of C6 glioma cells through phosphorylation of the myosin regulatory light chain. 1590 59

Gliomas are major tumors of the central nervous system with a wide spectrum of different tumor types. Ligand of Numb protein X (LNX) is PDZ domain containing protein that interacts with cell fate determinant Numb. cDNA microarray analysis was used to determine the expression of 13,939 genes in a set of 18 gliomas. It showed that human LNX was downregulated in 100% of gliomas including low- and high-grade ones, which was confirmed by Northern blot. In situ hybridization analysis revealed that LNX was lowly expressed in cytoplasm of glioma cells. Thus, LNX might act as a diagnostic marker and a potential therapeutic target for glioma. Two-hybrid screen in yeast was used to identify human LNX interacting proteins important for LNX function. It showed that human LNX interacted with Ski interacting protein (SKIP) via PDZ domains. The co-immunoprecipitation results suggested that LNX interacted with SKIP in HEK293 cells. LNX could affect the subcellular localization of Numb, which indicated that LNX might function as a molecular anchor that localized Numb to the subcellular site of its interaction with Notch. The presence of multiple protein binding domains involved in signal transduction and interaction with Numb and SKIP suggested an important role for LNX in tumorogenesis.
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PMID:Characterization of human LNX, a novel ligand of Numb protein X that is downregulated in human gliomas. 1600 21

The Bcl-2 nineteen kilodalton interacting protein 3 (BNIP3) is a hypoxia-inducible proapoptotic member of the Bcl-2 family that induces cell death by associating with the mitochondria. Under normal conditions, BNIP3 is expressed in skeletal muscle and in the brain at low levels. In many human solid tumors, BNIP3 is upregulated in hypoxic regions but paradoxically, this BNIP3 expression fails to induce cell death. Herein, we have determined that BNIP3 is primarily localized to the nucleus of glial cells of the normal human brain, as well as in the malignant glioma cell line U251. Upon exposure of U251 cells to hypoxia, BNIP3 expression in the cytoplasm increases and localizes with the mitochondria, contributing to induction of cell death. In contrast, when BNIP3 is forcibly over expressed in the nucleus, it fails to induce cell death. Expression of N-terminal BNIP3 (lacking the transmembrane and conserved domains) in U251 cells blocks hypoxia-induced cell death acting as a dominant negative protein by binding to wild-type BNIP3 and blocking its association with the mitochondria. In glioblastoma multiforme (GBM) tumors, BNIP3 expression is increased in hypoxic regions of the tumor and is primarily localized to the nucleus in approximately 80% of tumors. Hence, BNIP3 is sequestered in the nucleus within the brain but under hypoxic conditions, BNIP3 becomes primarily cytoplasmic, promoting cell death. In GBMs, BNIP3 expression is increased but it remains sequestered in the nucleus in hypoxic regions, thereby blocking BNIP3's ability to associate with the mitochondria, providing tumor cells with a possible survival advantage.
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PMID:The pro-cell death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia. 1621 54

Targeting chemotherapeutic agents directly to sites of DNA replication and repair within cancerous cells is problematic. This study attempts to address the issue of nuclear delivery of biologically active peptides with the potential to disrupt cancer cell growth. Herein, the protein transduction domain of the HIV-1 transactivator of transcription, Tat (Tat(48-60)), is used to deliver a cytotoxic peptide mimic of the cyclin-dependent kinase inhibitor, p21(WAF1/CIP1) into the nucleus. This construct, which we designate as Tat(48-60)-P10, contains the PCNA interacting protein (PIP) box. We demonstrate the utility of Tat(48-60) for peptide delivery to the nucleus and show that Tat(48-60)-P10 induces apoptosis specific to the inclusion of the wild type PIP box containing sequence. Colocalization of Tat(48-60)-P10 with nuclear PCNA was observed by immunofluorescence analysis, supporting the hypothesis that cytotoxicity is potentially related to disruption of nuclear PCNA function. The U251 and U373 glioma cell lines exhibited particular sensitivity to the construct.
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PMID:A sychnological cell penetrating peptide mimic of p21(WAF1/CIP1) is pro-apoptogenic. 1728 47

Pilocytic astrocytomas (PAs, WHO grade I) are the most common brain tumors in the pediatric and adolescent population, accounting for approximately one-fifth of central nervous system tumors. Because few consistent molecular alterations have been identified in PAs compared to higher grade gliomas, we performed array comparative genomic hybridization using two independent commercial array platforms. Although whole chromosomal gains and losses were not observed, a 1-Mb amplified region of 7q34 was detected in multiple patient samples using both array platforms. Copy-number gain was confirmed in an independent tumor sample set by quantitative PCR, and this amplification was correlated to both increased mRNA and protein expression of HIPK2, a homeobox-interacting protein kinase associated with malignancy, contained within this locus. Furthermore, overexpression of wild-type HIPK2, but not a kinase-inactive mutant, in a glioma cell line conferred a growth advantage in vitro. Collectively, these results illustrate the power and necessity of implementing high-resolution, multiple-platform genomic analyses to discover small and subtle, but functionally significant, genomic alterations associated with low-grade tumor formation and growth.
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PMID:High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. 1840 60

The Bcl-2 19 kDa interacting protein (BNIP3) is a pro-cell-death BH3-only member of the Bcl-2 family. We previously found that BNIP3 is localized to the nucleus in the majority of glioblastoma multiforme (GBM) tumors and fails to induce cell death. Herein, we have discovered that nuclear BNIP3 binds to the promoter of the apoptosis-inducing factor (AIF) gene and represses its expression. BNIP3 associates with PTB-associating splicing factor (PSF) and HDAC1 (histone deacetylase 1) contributing to transcriptional repression of the AIF gene. This BNIP3-mediated reduction in AIF expression leads to decreased temozolomide-induced apoptosis in glioma cells. Furthermore, nuclear BNIP3 expression in GBMs correlates with decreased AIF expression. Together, we have discovered a novel transcriptional repression function for BNIP3 causing reduced AIF expression and increased resistance to apoptosis. Thus, nuclear BNIP3 may confer a survival advantage to glioma cells and explain, in part, why BNIP3 is expressed at high levels in solid tumors, especially GBM.
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PMID:BNIP3 (Bcl-2 19 kDa interacting protein) acts as transcriptional repressor of apoptosis-inducing factor expression preventing cell death in human malignant gliomas. 1933 13

Oxidative stress by exposure to H(2)O(2) induces various types of cell death depending on cell type and conditions. We report herein on a study of the mechanisms underlying H(2)O(2)-induced cell death in C6 glioma cells. The findings show that H(2)O(2) triggers a caspase-independent autophagic cell death in these cells. The findings also show that H(2)O(2) induces the dephosphorylation of the mammalian target of rapamycin (mTOR) at Ser 2481 and the p70 ribosomal protein S6 kinase (p70S6K) at Thr389 in a Bcl-2/E1B 19kDa interacting protein 3 (BNIP3)-dependent manner. BNIP3 has the capacity to inhibit mTOR activity and mTOR inhibition plays a role in autophagic induction. This suggests that BNIP3 may mediate H(2)O(2)-induced autophagic cell death through the suppression of mTOR. The findings show that the down-regulation of BNIP3 by BNIP3 siRNA prevents C6 cells from undergoing H(2)O(2)-induced autophagic cell death. Collectively, these results suggest that H(2)O(2) induces autophagic cell death in C6 cells via the BNIP3-mediated suppression of the mTOR pathway.
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PMID:Hydrogen peroxide induces autophagic cell death in C6 glioma cells via BNIP3-mediated suppression of the mTOR pathway. 1953 16


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