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)

In Rat-1 fibroblasts epidermal growth factor (EGF), but not platelet-derived growth factor (PDGF) stimulates the activity of the c-Jun N-terminal kinase (JNK). Moreover, PDGF induced suppression of EGF-mediated JNK activation, apparently through protein kinase C (PKC) activation. Further analysis revealed that PKD was specifically activated by PDGF but not EGF in Rat-1 cells. In SF126 glioblastoma cells, however, EGF and PDGF synergistically activated JNK, while neither PDGF nor EGF stimulated PKD activity. In this cell line, overexpression of PKD blocked EGF- and PDGF-induced JNK activation. Mutational analysis further revealed that the EGFR mutant (T654/669E) was incapable of activating JNK and provided evidence that PKD-mediated dual phosphorylation of these critical threonine residues leads to suppression of EGF-induced JNK activation. Our results establish a novel crosstalk mechanism which allows signal integration and definition in cells with many different RTKs.
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PMID:Cell-type specific phosphorylation of threonines T654 and T669 by PKD defines the signal capacity of the EGF receptor. 1052 1

We used a genetic approach to characterize features of mitogen-activated protein kinase (MAPK) activation occurring as a consequence of expression of distinct erbB receptor combinations in transformed human cells. Kinase-deficient erbB proteins reduced epidermal growth factor (EGF)-induced tyrosine phosphorylation of endogenous Shc proteins and also reduced immediate and sustained EGF-induced ERK MAPK activities in human glioblastoma cells, although basal ERK MAPK activities were unaffected. Basal and EGF-induced JNK and p38 MAPK kinase activities were equivalent in parental cancer cells and EGFR-inhibited subclones. When ectopically overexpressed in murine fibroblasts and human glioblastoma cells, a constitutively activated human EGF receptor oncoprotein (deltaEGFR) induced EGF-independent elevation of basal ERK MAPK activity. Basal JNK MAPK kinase activity was also specifically induced by deltaEGFR, which correlated with increased phosphorylation of a 54-kDa JNK2 protein observed in deltaEGFR-containing cells. The JNK activities in response to DNA damage were comparably increased in cells containing wildtype EGFR or deltaEGFR. Consistent with the notion that transforming erbB complexes induce sustained and unregulated MAPK activities, coexpression of p185(neu) and EGFR proteins to levels sufficient to transform murine fibroblasts also resulted in prolonged EGF-induced ERK in vitro kinase activation. Transforming erbB complexes, including EGFR homodimers, deltaEGFR homodimers, and p185(neu)/EGFR heterodimers, appear to induce sustained, unattenuated activation of MAPK activities that may contribute to increased transformation and resistance to apoptosis in primary human glioblastoma cells.
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PMID:Sustained mitogen-activated protein kinase activation is induced by transforming erbB receptor complexes. 1054 32

Identification of the genes that are differentially expressed in brain tumor cells but not in normal brain cells is important for understanding the molecular basis of these neurological cancers and for defining possible targets for therapeutic intervention. In an effort to discover potentially antigenic proteins that may be involved in the malignant transformation and progression of human glioblastomas, a novel antibody-based approach was developed to identify and isolate gene products that are expressed in brain tumors versus normal brain tissue. Using this method, whereby tumor-specific antibodies were isolated and used to screen a glioblastoma cDNA expression library, 28 gene products were identified. Nine of these clones had homology to known gene products, and 19 were novel. The expression of these genes in multiple different human gliomas was then evaluated by cDNA microarray hybridization. One of the isolated clones had consistently higher levels of expression (3-30-fold) in brain tumors compared with normal brain. Northern blot analysis and in situ hybridization confirmed this differential overexpression. cDNA sequence analysis revealed that this gene was identical to a relatively new class of growth regulators known as granulins, which have tertiary structures resembling the epidermal growth factor-like proteins. The 2.1-kb granulin mRNA was expressed predominantly in glial tumors, with lower levels in spleen, kidney, and testes, whereas expression was not detected in non-tumor brain tissues. Functional assays using [3H]thymidine incorporation indicated that granulin may be a glial mitogen, as addition of synthetic granulin peptide to primary rat astrocytes and three different early-passage human glioblastoma cultures increased cell proliferation in vitro, whereas increasing concentrations of granulin antibody inhibited cell growth in a dose-dependent manner. The differential expression pattern, tissue distribution, and implication of this glioma-associated molecule in growth regulation suggest a potentially important role for granulin in the pathogenesis and/or malignant progression of primary brain neoplasms.
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PMID:Identification of a human glioma-associated growth factor gene, granulin, using differential immuno-absorption. 1072 98

In glioblastoma cells, inhibition of focal adhesion kinase (FAK) by the focal adhesion targeting domain attenuated epidermal growth factor receptor (EGFR) signaling, inhibiting epidermal growth factor-dependent migration. Although the EGFR-specific antagonist PD153035 increased caspase-3 activity, this was independent of FAK activity. Instead, the increase in apoptosis upon inhibition of FAK induced the aggregation of an NH(2)-terminal FAK fragment normally present in the nucleus. A recombinant NH(2)-terminal FAK construct was also targeted to the nucleus and aggregated in apoptotic cells upon coexpression with the focal adhesion targeting domain. Therefore, loss of FAK from the focal adhesions inhibits EGFR signaling at the cell membrane and transmits a proapoptotic signal to an NH(2)-terminal variant of FAK present in the nucleus.
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PMID:Loss of focal adhesion kinase (FAK) inhibits epidermal growth factor receptor-dependent migration and induces aggregation of nh(2)-terminal FAK in the nuclei of apoptotic glioblastoma cells. 1143 28

NELL1 and NELL2 encode cysteine-rich amino acid sequences including six epidermal growth factor-like motifs, which contain signal peptides at the N-terminals. The deduced amino acid sequences of both genes are 55% identical and their cysteine stretch structures are conserved. NELL1 is expressed in the brain and kidney, whereas NELL2 is expressed specifically in the brain. The cell lineage expressing NELLs in the nervous system was investigated in established cell lines and central nervous system tumor tissues obtained from patients by Northern blot and reverse transcriptase-polymerase chain reaction analyses. NELL1 and NELL2 were predominantly expressed in neuroblastoma cell lines and little expressed in glioblastoma cell lines. NELL1 and NELL2 were also expressed in central neurocytoma, medulloblastoma, and some astrocytic tumors. Immunohistochemical analysis revealed that NELL2 protein was localized in the cytoplasm of neurons. These results suggest that NELL2 is predominantly expressed in the neuronal cell lineage in the human nervous system. NELL1 is expressed mainly in tumors in the neuronal cell lineage.
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PMID:Brain specific human genes, NELL1 and NELL2, are predominantly expressed in neuroblastoma and other embryonal neuroepithelial tumors. 1180 83

Treatment of malignant brain tumors remains a clinical challenge. New treatment modalities are under investigation and among these are intratumoral infusion of immunotoxins that bind to specific cell surface molecules on the malignant cells. We have compared the efficacy of the 425.3-PE immunotoxin (which targets the epidermal growth factor [EGF] receptor) with the well-known immunotoxin Tfn-CRM107 (which targets the transferrin receptor), for the treatment of subcutaneous and intracranial human gliomas in nude animals. Bolus intratumoral administration of 1 microg Tfn-CRM107 or 425.3-PE into sc U87Mg tumors in nude mice reduced the tumor volume to 29 and 79%, respectively, of that in the control group 18 days after start of treatment. Higher doses of Tfn-CRM107 were toxic to the animals, whereas 425.3-PE was tolerated, with a dose-response relationship of up to 8 microg, a dose that reduced the tumor volume to 2% of control. In nude rats, treatment of intracerebral U87Mg tumors with Tfn-CRM107 proved ineffective and doses above 10 ng/animal were toxic to tumor-bearing rats. In contrast, intratumoral administration of 4 microg 425.3-PE increased symptom-free survival from 23 days to 40 days, with 2/9 surviving more than 90 days. We have recently shown that immunodeficient rats inoculated intracerebrally with precultured glioblastoma biopsy specimens develop highly infiltrative brain tumors. Direct interstitial infusion of immunotoxins into such tumors reduced the number of animals with detectable tumors at autopsy after 3 months, from 8/9 in the control animals to 4/6 and 2/6 in animals treated with Tfn-CRM107 and 425.3-PE, respectively. In conclusion, the anti-EGF receptor immunotoxin 425.3-PE exhibited promising efficacy, comparable to or better than that of Tfn-CRM107, an immunotoxin that in early clinical trials has been found to give responses in patients with brain tumors.
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PMID:Intratumoral immunotoxin treatment of human malignant brain tumors in immunodeficient animals. 1185 66

The tumor suppressor p16/CDKN2A/INK4a gene is frequently mutated, mostly by homozygous deletions in high-grade gliomas. Although the p16 protein suppresses cell proliferation primarily through inhibition of cell-cycle progression at the G1 phase, other phenotypic changes in glioma cells associated with p16INK4a alterations have not been fully described. To determine the roles of p16 alterations in glioma formation, we have established ecdysone-driven inducible p16 expression in the human glioblastoma cell line CL-4, which were derived from p16-null U87MG cells. Here we show that exogenous p16 expression in CL-4 cells results in morphological changes, with large and flattened cytoplasm, which are associated with increased formation of cytoplasmic actin-stress fibers and vinculin accumulation in the focal adhesion contacts. Adhesion of CL-4 cells to extracellular matrix proteins, such as laminin, fibronectin, and type IV collagen, significantly increased upon exogenous p16 expression, which correlated with increased expression of integrin alpha5 and alphav. Expression of a small GTP-binding protein, Rac, also decreased. Following epidermal growth factor stimulation, phosphorylation of MAP kinases ERK1 and 2 and induction of an early immediate gene product, c-Fos, were significantly reduced in CL-4 cells with p16 expression. These results suggest that the tumor suppressor p16 may exert its antitumor effects through modulation of multiple aspects of glioblastoma phenotypes, including proliferation, invasiveness, and responsiveness to extracellular growth stimuli.
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PMID:Phenotypic changes associated with exogenous expression of p16INK4a in human glioma cells. 1190 77

The epidermal growth factor (EGF) receptor is overexpressed in many cancers, and is under intensive investigation as a target for cancer therapy. Cancer cells have also been shown to express mutated EGF receptors; these are potentially highly specific targets for cancer therapeutics, as they have not been detected in any normal adult tissues. The most common of these mutant EGF receptors, EGFRvIII, is one in which amino acids 6 - 273 of the extracellular domain are deleted. This specific mutation is common in glioblastoma and in several other types of cancer, and has been shown to promote aggressive growth of tumors in vivo. The loss of part of the extracellular domain results in a receptor that has constitutive tyrosine kinase activity. Current evidence suggests that EGFRvIII has altered signalling properties compared to normal EGF receptor. The mutation in EGFRvIII also creates a new, cancer cell-specific epitope. This epitope is extracellular and therefore represents a very promising target for antibody-directed therapeutics. This review covers our current understanding of the properties of EGFRvIII, and recent developments in the characterization and therapeutic application of EGFRvIII-specific antibodies.
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PMID:Mutant epidermal growth factor receptors as targets for cancer therapy. 1218 12

EGFRvIII is a mutant epidermal growth factor that promotes aggressive growth of glioblastomas. We made a plasmid that directed the expression of an EGFRvIII with three copies of the Flag epitope at its amino terminus. Flag-tagged EGFRvIII was expressed at the same levels as unmodified EGFRvIII, and showed the same subcellular localization. However, the Flag epitope could only be detected on EGFRvIII present in the endoplasmic reticulum; the epitope was covalently modified during trafficking of the receptor through the Golgi so that it was no longer recognized by anti-Flag antibody. This property was exploited to selectively purify nascent EGFRvIII from glioblastoma cells. Nascent EGFRvIII was found to copurify with a set of other proteins, identified by mass spectrometry as the two endoplasmic reticulum chaperones Grp94 and BiP, and the two cytosolic chaperones Hsc70 and Hsp90. The Hsp90-associated chaperone Cdc37 also co-purified with EGFRvIII, suggesting that Hsp90 binds EGFRvIII as a complex with this protein. Geldanamycin and radicicol, two chemically unrelated inhibitors of Hsp90, decreased the expression of EGFRvIII in glioblastoma cells. These studies show that nascent EGFRvIII in the endoplasmic reticulum associates with Hsp90 and Cdc37, and that the Hsp90 association is necessary to maintain expression of EGFRvIII.
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PMID:Interaction of Hsp90 with the nascent form of the mutant epidermal growth factor receptor EGFRvIII. 1247 Oct 35

The granulin-epithelin precursor, progranulin, PC-cell-derived growth factor or acrogranin, is a high molecular weight secreted mitogen. It is abundantly expressed in rapidly cycling epithelial cells, in the immune system and in neurons, such as cerebellar Purkinje cells. Progranulin contributes to tumorigenesis in diverse cancers, including breast cancer, clear cell renal carcinoma, invasive ovarian carcinoma and glioblastoma. It regulates the rate of epithelial cell division in responsive epithelial cells, and confers an invasive phenotype on these cells. It is involved in the wound response. During embryogenesis, progranulin accelerates blastocyst formation, and is a growth factor for trophectodermal cells. In the neonate, progranulin, regulates the hormone-dependent virilization of the hypothalamus. It activates phosphorylation of Shc, and p44/42 MAPK (mitogen activated protein kinase) in the ERK (extracellular regulated kinase) signaling pathway; PI3K (phosophatidyl inositol-3-kinase), AKT/protein kinase B, and p70S6kinase in the phosophatidyl inositol-3-kinase pathway; and focal adhesion kinase in the adhesion/motility pathway. The signaling properties of progranulin are apparently similar to those of classic growth factors, but the functional properties of progranulin distinguish it from these molecules. Deleting the insulin-like growth factor I receptor from murine embryonic fibroblasts blocks proliferation in response to all classic growth factors, such as epidermal growth factor, or platelet-derived growth factor, whereas progranulin retains mitotic activity on these cells. The defined biological actions of progranulin probably represent a small fraction of its overall functions. Transcriptome analyses show that the progranulin gene is induced in numerous situations that vary from obesity to the transcriptional response of cells to antineoplastic drugs. Here, the biological roles of progranulin will be reviewed, with an emphasis on cancer and cell proliferation.
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PMID:Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis. 1297 94


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