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Murine double minute 2 as a therapeutic target for radiation sensitization of lung cancer.
Cao C, Shinohara ET, Niermann KJ, Donnelly EF, Chen X, Hallahan DE, Lu B
(2005) Mol Cancer Ther 4: 1137-45
MeSH Terms: Animals, Apoptosis, Cell Cycle Proteins, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p21, Endothelium, Vascular, Humans, Lung Neoplasms, Mice, Nuclear Proteins, Oligonucleotides, Antisense, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Radiation-Sensitizing Agents, Transfection, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Umbilical Cord, Up-Regulation
Show Abstract · Added February 28, 2014
Murine double minute 2 (MDM2) inhibits p53-mediated functions, which are essential for therapies using DNA-damaging agents. The purpose of this study was to determine whether MDM2 inhibition enhances the radiosensitivity of a lung cancer model. The effects of MDM2 inhibition on tumor vasculature were also studied. Transient transfection of H460 lung cancer cells and human umbilical vascular endothelial cells (HUVEC) with antisense oligonucleotides (ASODN) against MDM2 resulted in a reduced level of MDM2 and increased levels of p21 and p53. Clonogenic assays showed that inhibition of MDM2 greatly decreased cell survival following irradiation. Quantification of apoptotic cells by 7-aminoactinomycin D staining and of senescent cells by X-gal staining showed that both processes were significantly increased in H460 cells treated with MDM2-specific ASODN and radiation. H460 xenografts that were treated with MDM2 ASODN plus radiotherapy also showed significant growth delay (P < 0.001) and increased apoptosis by terminal deoxynucleotidyl transferase-mediated nick end labeling staining. HUVECs transfected with MDM2-specific ASODN showed impaired viability and migration with decreased tube formation. Doppler studies showed that tumor blood flow was compromised when H460 xenografts were treated with MDM2-specific ASODN and radiation. A combination of radiotherapy and inhibition of MDM2 through the antisense approach results in improved tumor control in the H460 lung cancer model. This implies that a similar strategy should be investigated among patients with locally advanced lung cancer, receiving thoracic radiotherapy.
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19 MeSH Terms
Tumor necrosis factor-alpha induction of endothelial ephrin A1 expression is mediated by a p38 MAPK- and SAPK/JNK-dependent but nuclear factor-kappa B-independent mechanism.
Cheng N, Chen J
(2001) J Biol Chem 276: 13771-7
MeSH Terms: Adenoviridae, Antigens, CD, Blotting, Northern, Blotting, Western, Cells, Cultured, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Endothelium, Vascular, Enzyme Activation, Enzyme Inhibitors, Ephrin-A1, Flavonoids, Gene Expression Regulation, Enzymologic, Genes, Dominant, Humans, Kinetics, Ligands, Mitogen-Activated Protein Kinase 9, Mitogen-Activated Protein Kinases, Models, Biological, NF-kappa B, Phosphotransferases, Protein Biosynthesis, Protein Isoforms, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Signal Transduction, Time Factors, Tumor Necrosis Factor-alpha, Umbilical Cord, Up-Regulation, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 5, 2014
Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine that induces a broad spectrum of responses including angiogenesis. Angiogenesis promoted by TNF-alpha is mediated, at least in part, by ephrin A1, a member of the ligand family for Eph receptor tyrosine kinases. Although TNF-alpha induces ephrin A1 expression in endothelial cells, the signaling pathways mediating ephrin A1 induction remain unknown. In this study, we investigated the signaling mechanisms of TNF-alpha-dependent induction of ephrin A1 in endothelial cells. Both TNFR1 and TNFR2 appear to be involved in regulating ephrin A1 expression in endothelial cells, because neutralizing antibodies to either TNFR1 or TNFR2 inhibited TNF-alpha-induced ephrin A1 expression. Inhibition of nuclear factor-kappaB (NF-kappaB) activation by a trans-dominant inhibitory isoform of mutant IkappaBalpha did not affect ephrin A1 induction, suggesting that NF-kappaB proteins are not major regulators of ephrin A1 expression. In contrast, ephrin A1 induction was blocked by inhibition of p38 mitogen-activated protein kinase (MAPK) or SAPK/JNK, but not p42/44 MAPK, using either selective chemical inhibitors or dominant-negative forms of p38 MAPK or TNF receptor-associated factor 2. These findings indicate that TNF-alpha-induced ephrin A1 expression is mediated through JNK and p38 MAPK signaling pathways. Taken together, the results of our study demonstrated that induction of ephrin A1 in endothelial cells by TNF-alpha is mediated through both p38 MAPK and SAPK/JNK, but not p42/44 MAPK or NF-kappaB, pathways.
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33 MeSH Terms
Preparation and properties of a hemoglobin containing heme only in gamma subunits.
Gondko R, Obrebska MJ, Waterman MR
(1974) Biochem Biophys Res Commun 56: 444-50
MeSH Terms: Apoproteins, Carbon Monoxide, Carboxyhemoglobin, Chromatography, Ion Exchange, Electrophoresis, Starch Gel, Female, Fetal Hemoglobin, Hemoglobins, Humans, Mercuribenzoates, Oxygen, Oxyhemoglobins, Peptides, Pregnancy, Protein Binding, Spectrophotometry, Spectrophotometry, Ultraviolet, Umbilical Cord
Added February 12, 2015
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18 MeSH Terms
Effect of ligands on alkaline denaturation of fetal hemoglobin and isolated gamma subunits.
Painter TD, Waterman MR
(1973) Biochem Biophys Res Commun 55: 812-7
MeSH Terms: Carboxyhemoglobin, Chromatography, Ion Exchange, Electrophoresis, Disc, Female, Fetal Hemoglobin, Humans, Hydrogen-Ion Concentration, Iron, Kinetics, Ligands, Mercuribenzoates, Methemoglobin, Peptides, Pregnancy, Protein Denaturation, Spectrophotometry, Time Factors, Umbilical Cord
Added February 12, 2015
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18 MeSH Terms