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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The met oncogene activated in vitro by treatment of a human osteogenic sarcoma (HOS) cell line with N-methyl-N'-nitronitrosoguanidine (MNNG) is related to the tyrosine kinase gene family. Probes from the met oncogene locus recognize two distinct transcripts of 9.0 kb and 10.0 kb which are independently expressed in a cell-type-specific fashion. While the met proto-oncogene locus expresses the 9.0 kb RNA and maps to human chromosome 7q21-31, the locus expressing the 10.0 kb RNA, (tpr; translocated promoter region) maps to human chromosome 1. Both MNNG-HOS cells and met NIH 3T3 transformants express a novel 5.0 kb RNA which represents a hybrid transcript with 5' sequences derived from tpr and 3' sequences from the met proto-oncogene. Treating HOS cells in vitro with MNNG, a known clastogenic carcinogen, resulted in fusion of two chromosomally disparate loci, met and tpr, generating the active met oncogene.
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PMID:Mechanism of met oncogene activation. 242 52

We previously demonstrated that a high-molecular-weight glycoprotein could be immunoprecipitated from metabolically labeled U-2 OS cells with platelet-derived growth factor (PDGF) antiserum and that it appears to be derived from a different precursor than is the 30 kD PDGF-like mitogen produced by these cells. These findings were unexpected, since the molecular weight of this glycoprotein is too large to be encoded by the PDGF structural genes. From experiments with metabolically labeled U-2 OS human osteosarcoma, fibroblasts, and NRK cells, we report here that a 185 kD protein immunoprecipitated with PDGF antiserum has the following characteristics. 1) It is a PDGF binding protein that is unrelated to alpha 2-macroglobulin. 2) It is phosphorylated in response to PDGF stimulation. 3) It is immunoprecipitated by phosphotyrosine antibodies. 4) It is not a substrate of epidermal growth factor-induced tyrosine kinase activity. These studies indicate that high-molecular-weight proteins immunoprecipitated by antiserum to PDGF represent a complex between PDGF and a binding protein capable of being phosphorylated by a PDGF-induced tyrosine kinase. These characteristics are identical to those of the PDGF receptor.
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PMID:Characterization of a high-molecular-weight protein immunoprecipitated by platelet-derived growth factor antisera. 246 74

The growth of MG63 human osteosarcoma cell line in 5% serum is stimulated by epidermal growth factor (EGF), platelet-derived growth factor (PDGF), or heparin-binding growth factor-1 (HBGF-1). The mitogenic effect of EGF and PDGF is completely blocked by TFG-beta at 1 ng per ml and the effect of HBGF-1 is attenuated by 75-80%. Treatment of MG63 cells with TGF-beta reduces HBGF-1 receptor binding affinity from 1.24 x 10(-11) M to 3.51 x 10(-11) M with no change on the receptor number (1.1 x 10(3) per cell). The receptor-binding affinity of EGF and PDGF is not altered by TGF-beta treatment; however, the number of EGF receptor is increased by 25%. Both EGF and PDGF stimulate MG63 cellular tyrosine kinase activity, and such stimulation is inhibited by TGF-beta pretreatment. No change in the cellular protein tyrosine phosphorylation pattern can be detected in HBGF-1-stimulated cells with and without TGF-beta pretreatment. These data suggest that TGF-beta inhibits EGF and PDGF mitogenicity by blocking EGF- and PDGF-stimulated tyrosine kinase activity and attenuates HBGF-1 mitogenicity by decreasing its receptor affinity.
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PMID:Differential inhibitory effects of TGF-beta on EGF-, PDGF-, and HBGF-1-stimulated MG63 human osteosarcoma cell growth: possible involvement of growth factor interactions at the receptor and postreceptor levels. 247 12

Previous studies have shown that suramin reveals specific PDGF binding sites on U-2 OS human osteosarcoma cells. Studies presented here indicate that U-2 OS cells pretreated with suramin internalize and degrade 125I-PDGF and respond to PDGF by increased tyrosine kinase activity and amino acid transport. However, DNA synthesis in these cells is not reduced by incubation with the PDGF blocking agent suramin and is not stimulated by exogenous PDGF. These data indicate that U-2 OS cells possess functional PDGF receptors but that high levels of DNA synthesis in these cells is unrelated to the binding of secreted PDGF to these cell surface receptors. Thus, it is unlikely that the PDGF mitogen produced by U-2 OS cells stimulates proliferation through an autocrine mechanism involving secretion and subsequent binding to PDGF receptors.
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PMID:DNA synthesis in U-2 OS human osteosarcoma cells is independent of PDGF binding to functional cell surface receptors. 284 Apr 34

The platelet-derived growth factor receptor (PDGF-R), a 180-kDa single-chain polypeptide, was purified from membranes of the human osteogenic sarcoma cell line MG-63. Purification was achieved by treatment of membranes with PDGF and ATP, followed by solubilization with nonionic detergent and successive chromatography on solid-phase anti-phosphotyrosine monoclonal antibody and DEAE-cellulose. The PDGF-R, which was estimated to be 50-80% pure by NaDodSO4/polyacrylamide gel electrophoresis of 32P-labeled preparations, was free of contaminating epidermal growth factor receptor and had no detectable phosphatase activity. It specifically bound 125I-labeled PDGF, a reaction quantified by binding of the ligand-PDGF-R complex to the anti-phosphotyrosine antibody. The purified receptor displayed PDGF-stimulatable tyrosine kinase activity, assayed by autophosphorylation of PDGF-R at tyrosine residues and by phosphorylation of angiotensin II. The Km for ATP in the autophosphorylation reaction was 7.5 microM. Addition of PDGF did not change the Km but increased the Vmax 1.7-fold.
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PMID:Purified human platelet-derived growth factor receptor has ligand-stimulated tyrosine kinase activity. 301 45

Prolonged exposure of a nontumorigenic human osteogenic sarcoma cell line (HOS) with the direct acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) gave rise to morphologically transformed cells which were tumorigenic in nude mice and termed MNNG-HOS. We have shown that DNA from MNNG-HOS cells will transform NIH/3T3 cells and have isolated greater than 35 kb of human DNA containing an oncogene, termed met. The activated met oncogene expresses a novel 5.0 kb RNA transcript which is a hybrid RNA derived from a DNA rearrangement involving two distinct genetic loci termed met and tpr (translocated promoter region). The met proto-oncogene has been localized to 7q21-q31 by in situ hybridization. This locus expresses a 9.0 kb RNA in fibroblast and epithelial cell lines, but is not commonly expressed in cell lines derived from the hematopoietic cell lineage. In contrast, the tpr locus is on chromosome 1, and expresses a 10.0 kb RNA in all human cell lines tested. The novel 5.0 kb met oncogene RNA is 3' co-terminal with the 9.0 kb met proto-oncogene RNA, while the 5' portion of this RNA uses at least two exons derived from the 10.0 kb tpr RNA. These exons are small and are presumably in the promoter region of both tpr and tpr-met transcripts. Nucleotide sequence analysis of the 3' end of met shows that it is a member of the tyrosine kinase family of genes. Peptide antibody to the C-terminal coding region of met immunoprecipitates a 65 kilodalton (kd) polypeptide (p65) in both MNNG-HOS cells and met transformed NIH/3T3 cells. This product also has tyrosine kinase activity in vitro and is presumed to correspond to the tpr-met product. The same antibody detects three larger met-related polypeptides of 160, 140, and 110 kd in human fibroblasts and epithelial cells by in vivo labeling with [35S]methionine. However, only one of the three met proto-oncogene polypeptides, p140, appears to be phosphorylated in the in vitro kinase assay. High levels of in vitro 32P incorporation into p140 met are observed in 4 out of 30 human epithelial cancer cell lines tested. Activation of the met oncogene in MNNG-HOS cells results from a DNA rearrangement possibly mediated in vitro by MNNG. The mode of activation of met may therefore be similar to the epidermal growth factor (EGF)R/v-erbB oncogene; or the bcr/c-abl rearrangement present in the Philadelphia chromosome translocation which is found in chronic myelogenous leukemias.
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PMID:The human met oncogene is a member of the tyrosine kinase family. 333 11

Preincubation of Dunn osteosarcoma cells for 1 h with both 100 nM of staurosporine and 10 micrograms/ml of genistein resulted in a significant decrease in the motility stimulated by autocrine motility factor (AMF), whereas these reagents did not affect the basal motility and proliferation at these concentrations. The effect of the agents on the stimulated motility was both dose- and time-dependent. The motility stimulated by the anti-AMF receptor mAb was also inhibited. In contrast, H-8 had a negligible effect upon the stimulated motility. These data suggest that both kinase C and tyrosine kinase play a role in AMF-stimulated cell motility, while protein kinase A, which is selectively associated with the adenylate cyclase pathway, may not be required for the stimulation.
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PMID:Effects of protein kinase inhibitors on the cell motility stimulated by autocrine motility factor. 803 8

U2OS Dr1 cells, originating from a human osteosarcoma, are resistant to the intracellular action of diphtheria toxin but contain toxin receptors on their surfaces. These cells do not have detectable amounts of fibroblast growth factor receptors. When these cells were transfected with fibroblast growth factor receptor 4, the addition of acidic fibroblast growth factor to the medium induced tyrosine phosphorylation, DNA synthesis, and cell proliferation. A considerable fraction of the cell-associated growth factor was found in the nuclear fraction. When the growth factor was fused to the diphtheria toxin A fragment, it was still bound to the growth factor receptor and induced tyrosine phosphorylation but did not induce DNA synthesis or cell proliferation, nor was any fusion protein recovered in the nuclear fraction. On the other hand, when the fusion protein was associated with the diphtheria toxin B fragment to allow translocation to the cytosol by the toxin pathway, the fusion protein was targeted to the nucleus and stimulated both DNA synthesis and cell proliferation. In untransfected cells containing toxin receptors but not fibroblast growth factor receptors, the fusion protein was translocated to the cytosol and targeted to the nucleus, but in this case, it stimulated only DNA synthesis. These data indicate that the following two signals are required to stimulate cell proliferation in transfected U2OS Dr1 cells: the tyrosine kinase signal from the activated fibroblast growth factor receptor and translocation of the growth factor into the cell.
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PMID:Stimulation of proliferation of a human osteosarcoma cell line by exogenous acidic fibroblast growth factor requires both activation of receptor tyrosine kinase and growth factor internalization. 852 4

The maintenance of cell volume involves transduction of a volume-sensing signal into effectors of volume-regulatory transporters. After exposure to anisotonic conditions, cells undergo compensatory volume changes that are mediated by active transport and passive movement of ions and solutes. Intracellular pH (pHi) homeostasis may be compromised during these processes. We have studied pHi and some of the signal transduction mechanisms involved in the regulatory volume decrease (RVD) that occurs after exposure to hypoosmolar conditions in rat osteosarcoma cells, ROS 17/2.8. Cells were loaded with BCECF; pHi and cell volume were estimated by dual excitation ratio fluorimetry. Swelling of cells in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffered hypotonic medium induced a rapid cell swelling followed by an incomplete RVD of approximately 30% in suspended (i.e., round) cells and approximately 60% in attached (i.e., spread) cells that was independent of subpassage number. RVD was inhibited by ouabain, valinomycin, and high external [K+], all of which should reduce the cell membrane electrochemical gradient for K+. Inhibition of RVD was induced also by decreasing intracellular [Ca2+] with BAPTA-AM and by depletion of Cl-, indicating the role of calcium-regulated K+ and Cl- efflux during RVD. Depolymerization of actin filaments by cytochalasin D prolonged the RVD three-fold and nonspecific activation of GTP-binding proteins up-regulated RVD. In attached cells the hypoosmolar-induced swelling caused a large reduction in pHi (approximately 0.7 units), which was sustained as long as cells were in hypoosmotic medium. The reduction of pHi induced by cell swelling was inhibited by Na(+)-free extracellular medium, ouabain, the tyrosine kinase inhibitor genistein, and to a lesser extent by Cl(-)-free medium. However, amiloride failed to inhibit the hypoosmolar-induced reduction of pHi. Collectively these data indicate that RVD of ROS 17/2.8 cells in HEPES-buffered medium is dependent on conductive efflux of K+ and Cl- that is regulated by cell shape, actin, and GTP-binding proteins. The sustained inhibition of pHi homeostasis induced by cell swelling may reflect the existence of cell volume sensing mechanisms that operate through tyrosine kinases to regulate pHi.
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PMID:Regulation of cell volume and intracellular pH in hyposmotically swollen rat osteosarcoma cells. 870 24

A constitutively active form of fibroblast growth factor 2 (FGFR2) was identified in rat osteosarcoma (ROS) cells by an expression cloning strategy. Unlike other tyrosine kinase receptors activated by N-terminal truncation in tumors, this receptor, FGFR2-ROS, contains an altered C terminus generated from chromosomal rearrangement with a novel gene, designated FGFR activating gene 1 (FRAG1). While the removal of the C terminus slightly activates FGFR2, the presence of the FRAG1 sequence drastically stimulates the transforming activity and autophosphorylation of the receptor. FGFR2-ROS is expressed as a unusually large protein and is highly phosphorylated in NIH 3T3 transfectants. FRAG1 is ubiquitously expressed and encodes a predicted protein of 28 kDa lacking significant structural similarity to known proteins. Epitope-tagged FRAG1 protein showed a perinuclear localization by immunofluorescence staining. The highly activated state of FGFR2-ROS appears to be attributed to constitutive dimer formation and higher phosphorylation level as well as possibly altered subcellular localization. These results indicate a unique mechanism of receptor activation by a C terminus alteration through a chromosomal fusion with FRAG1.
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PMID:FRAG1, a gene that potently activates fibroblast growth factor receptor by C-terminal fusion through chromosomal rearrangement. 879 35


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