Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we reported the establishment of two transplantable osteosarcomas, one induced by local application of a carcinogen, 4-hydroxyamino quinoline 1-oxide(4-HAQO), and another which developed spontaneously in rats, and their subdivision into four lines with high and low metastatic potential to the lung. In the present study, mutations of p53 and Ki-ras genes were investigated by PCR and SSCP followed by direct sequencing, and the amplification of the mdm2 gene was assessed by Southern blot analysis. Mutations of p53 in exon 7 were detected in 4-HAQO-induced transplantable osteosarcomas, but not their spontaneous counterparts, irrespective of the metastatic potentials. Direct sequencing revealed a CGC to CAC transition with an amino acid change of Arg to His, at codon 246. Neither Ki-ras mutations nor mdm2 amplification were detected in any of the transplantable tumors. The results suggest that while p53 mutations occurred during osteosarcoma development by 4-HAQO without mdm2 amplification and Ki-ras mutation does not contribute to osteosarcoma development in rats.
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PMID:p53 mutation and absence of mdm2 amplification and Ki-ras mutation in 4-hydroxyamino quinoline 1-oxide induced transplantable osteosarcomas in rats. 902 63

At the histological level, the differential diagnosis of osteoblastic bone tumors is characterized by several problems that cannot be solved by conventional histological methods including immunohistology. Differentiating aneurysmal bone cyst from telangiectatic osteosarcoma or giant cell tumor from giant cell-containing highly malignant osteosarcoma are only two examples reflecting the complexity of this field. To develop a new approach to these diagnostic problems, we analyzed the genetic instability in a large number of bone-forming tumor-like lesions as well as in benign and malignant osteoblastic tumors. Our research concentrated on genetic alterations in cell cycle regulator genes: mutations in the p53 gene and ras gene, loss of heterozygosity at the p53, p16 and Rb-locus, and amplification of the mdm2-gene and the c-myc-gene. In addition to cell cycle regulators, the telomerase activity has also been analyzed. The results show that the number of genetic alterations increases with the malignancy of the tumors. The highest number of genetic alterations could thus be found in conventional intraosseous osteosarcoma. In tumor-like lesions, genetic alterations have rarely been observed. The results of this study show that analyzing the genetic instability probably contributes to an improvement in the differential diagnosis of osteoblastic tumors.
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PMID:Genetic instability in osteoblastic tumors of the skeletal system. 982 Aug 62

In the histological differential diagnosis of osteoblastic bone tumors, several problems could not have been solved by conventional histological methods including immunohistology. Some well-known examples are the differential diagnosis between aneurysmal bone cyst and telangiectatic osteosarcoma and giant cell tumor versus giant cell-containing highly malignant osteosarcoma. As a new approach to these diagnostic problems, we analyzed the genetic instability in a larger number of bone-forming tumor-like lesions, benign and malignant osteoblastic tumors. Analysis focused on genetic alterations in cell cycle regulator genes: Mutations in the p53 gene and ras gene, loss of heterozygosity at the p53, p16 and Rb-locus, and amplification of the mdm2 gene and the c-myc-gene. In addition to cell cycle regulators, the telomerase activity has also been analyzed. The results show that the number of genetic alterations increases with the malignancy of the tumors. The highest number of genetic alterations could thus be found in conventional intraosseous osteosarcoma. In tumor-like lesions, genetic alterations have rarely been observed. The results of this study show that the analysis of genetic instability will probably contribute to an improved differential diagnosis of osteoblastic tumors.
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PMID:[Genetic instability in osteoblastic tumors of the skeletal system]. 1009 25

The nuclear phosphoprotein c-Jun is a major component of the AP-1 transcription factor, whose activity is augmented by many oncogenes. An important mechanism to stimulate AP-1 function is N-terminal phosphorylation of c-Jun at the serine residues 63 and 73 by the c-JunN-terminal kinases (JNKs). Mice and cells harboring a mutant allele of c-jun, which has the JNK phosphoacceptor serines changed to alanines (junAA), were used to determine the function of c-Jun N-terminal phosphorylation (JNP) during oncogenic transformation in vitro and in vivo. JunAA immortalized fibroblasts expressing v-ras and v-fos showed reduced tumorigenicity in nude mice, but the efficiency of v-src transformation was unaffected by the lack of JNP. To assess the significance of JNP in tumour development in vivo, two transgenic mouse tumour models were employed. Skin tumour development caused by constitutive activation of the ras pathway by K5-SOS-F expression and c-fos-induced osteosarcoma formation were impaired in mice lacking JNP. Inhibition of JNP may, therefore, be a novel therapeutic strategy to inhibit tumour growth in vivo. Oncogene (2000).
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PMID:Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation. 1085 Oct 65

The nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) is an RNA-dependent RNA polymerase (RdRp) which plays an essential role in viral RNA replication. Antibodies that specifically recognize NS5B will have utilities in monitoring NS5B production and subcellular localization, as well as in structure-function studies. In this report, three mouse monoclonal antibodies (mAbs), 16A9C9, 16D9A4 and 20A12C7, against a recombinant NS5B protein (genotype 1a, H-77 strain) were produced. These mAbs specifically recognize HCV NS5B, but not RdRps of polivirus (PV), bovine viral diarrhea virus (BVDV) or GB virus B (GBV-B). The mAbs can readily detect NS5B in cellular lysates of human osteosarcoma Saos2 cells constitutively expressing the nonstructural region of HCV (NS3-NS4A-NS4B-NS5A-NS5B). NS5B proteins of different HCV genotypes/subtypes (1a, 1b, 2a, 2c, 5a) showed varied affinity for these mAbs. Interestingly, the epitopes for the mAbs were mapped to the palm subdomain (amino acid 188-370) of the HCV RdRp as determined by immunoblotting analysis of a panel of HCV/GBV-B chimeric NS5B proteins. The binding site was mapped between amino acid 231 and 267 of NS5B for 16A9C9, and between 282 and 372 for 16D9A4 and 20A12C7. Furthermore, these mAbs showed no inhibitory effect on the NS5B polymerase activity in vitro.
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PMID:Characterization of monoclonal antibodies that specifically recognize the palm subdomain of hepatitis C virus nonstructural protein 5B polymerase. 1132 72

Recently, we cloned a cDNA encoding a novel mouse protein, named A-C1, by differential display between two mouse cell lines, embryonic fibroblast C3H10T1/2 and chondrogenic ATDC5. Mouse A-C1 has homology with a ras-responsive gene, rat Ha-rev107 (Hrasls), and modulates a Ha-ras-mediated signaling pathway. Here, we report a cDNA encoding a human homolog of mouse A-C1. The deduced amino acid sequence of human A-C1 consists of 168 amino acids, and shows 83% identity with that of mouse A-C1. Human A-C1 mRNA was expressed in skeletal muscle, testis, heart, brain, and thyroid in vivo. Moreover, expression of human A-C1 mRNA was detected at a high level in human osteosarcoma-derived U2OS cells in vitro. By FISH analysis the human A-C1 gene (HRASLS) was mapped to human chromosome 3q28--> q29.
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PMID:Isolation, characterization, and chromosome mapping of a human A-C1 Ha-Ras suppressor gene (HRASLS). 1147 75

Most osteosarcomas are highly aggressive malignancies characterized by a complex pattern of chromosome abnormalities. However, a subgroup of low-grade, parosteal tumors exhibits a relatively simple aberration pattern dominated by ring chromosomes carrying amplified material from chromosome 12. To assess whether sequences from this chromosome were differentially amplified in low- and high-grade osteosarcomas, copy numbers of the CCND2, ETV6, KRAS2, and D12S85 regions in 12p and the MDM2 region in 12q were evaluated by interphase or metaphase fluorescence in situ hybridization (FISH) in 24 osteosarcomas. Amplification of MDM2 was detected in all five low-grade and four high-grade osteosarcomas, all of which showed ring chromosomes. An overrepresentation of 12p sequences was found in 1/5 low-grade and in 9/19 high-grade tumors. Multicolor single-copy FISH analysis of metaphase cells from six high-grade tumors showed that extra 12p material either occurred together with MDM2 in ring chromosomes or was scattered over the genome as a result of complex structural rearrangements. Most tumors (8/10) not containing amplification of the assessed chromosome 12 loci exhibited a nondiploid pattern at evaluation with probes for centromeric alpha satellite sequences. These findings indicate that gain of sequences from the short arm of chromosome 12 could be a possible genetic pathway in the development of aggressive osteosarcoma.
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PMID:Differentially amplified chromosome 12 sequences in low- and high-grade osteosarcoma. 1179 39

Tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 have growth-stimulating activity for a wide range of cell types. Ras, which comprises a family of three members, i.e, Ha-Ras, Ki-Ras, and H-Ras, is known to participate in growth control in all its facets, including cell proliferation, transformation, differentiation, and apoptosis. In this study, we tested the hypothesis that Ras might be involved in the cell growth-promoting activity of TIMPs. Using MG-63 human osteosarcoma cells, we demonstrated that both TIMP-1 and TIMP-2 caused an increase in the Ras-GTP level in a dose-dependent manner. Our previous results indicated that TIMP-1 activity is mediated through the tyrosine kinase (TYK)/mitogen-activated protein kinase (MAPK) pathway. Here, we demonstrated that Ras activation by TIMP-1 was inhibited by a specific TYK inhibitor, herbimycin A, suggesting that the TYK/MAPK signaling pathway was involved in Ras activation by TIMP-1. However, the activation of Ras by TIMP-2 was inhibited by an inhibitor specific for cyclic AMP-dependent protein kinase (PKA), H89, suggesting the involvement of the PKA-mediated pathway. Furthermore, TIMP-2 promoted the formation of a complex between Ras-GTP and phosphoinositide 3-kinase.
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PMID:Both tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 activate Ras but through different pathways. 1214 51

IGF-I stimulates cell division in numerous cell types after activation of the IGF-I receptor, a transmembrane heterotetramer linked to the ras-raf-MAPK and phosphatidylinositol 3-kinase signaling pathways. The WT1 Wilms' tumor suppressor is a zinc finger-containing transcription factor that is involved in a number of developmental processes, as well as in the etiology of certain neoplasias. In the present study, we demonstrated that IGF-I reduced WT1 expression in osteosarcoma-derived Saos-2 cells in a time- and dose-dependent manner. This effect was mediated through the MAPK signaling pathway, as shown by the ability of the specific inhibitor UO126 to abrogate IGF-I action. Furthermore, the effect of IGF-I involved repression of transcription from the WT1 gene promoter, as demonstrated using transient transfection assays. Taken together, our results suggest that the WT1 gene is a novel downstream target for IGF-I action. Reduced levels of WT1 may facilitate IGF-I-stimulated cell cycle progression. Most importantly, inhibition of WT1 gene expression by IGF-I may have significant implications in terms of cancer initiation and/or progression.
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PMID:The WT1 Wilms' tumor suppressor gene: a novel target for insulin-like growth factor-I action. 1296 88

IFN-alpha combined with ribavirin is used for the treatment of chronic hepatitis C. However, HCV has mechanisms to resist the antiviral actions of IFN-alpha. In order to study the molecular mechanisms of this resistance, the effect of HCV gene expression on IFN-induced nuclear import of STAT transcription factors and the expression of antiviral MxA protein were studied. In transiently transfected hepatoma cells, HCV core and NS5A proteins clearly inhibited the nuclear import of STAT1 and MxA protein expression (core only), whereas other viral proteins had only a marginal effect. To confirm these observations, human osteosarcoma-derived cell lines, which inducibly express HCV core protein, the entire structural region (core-E1-E2-p7), the NS3-4A complex, NS4B, NS5A, or NS5B proteins were also used. IFN-induced nuclear accumulation of STAT1 was almost completely and STAT2 was partially blocked in cell lines expressing high levels of HCV core protein. Subsequently, in these cells, IFN-alpha-induced MxB protein expression was decreased. Tumor necrosis factor-alpha (TNF-alpha)-induced nuclear import of NF-kappaB was only weakly or not at all inhibited, suggesting that the nuclear import machinery in general was not impaired. The results demonstrate a novel mechanism by which HCV gene expression may interfere with IFN-mediated host defence systems.
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PMID:Expression of hepatitis C virus core protein inhibits interferon-induced nuclear import of STATs. 1522 97


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