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)

The rat osteosarcoma cell line UMR 106-01 is a commonly used model system for the study of osteoblast function. However, it also expresses a phenotype characteristic of transformed cells. To test whether the latter could be accounted for by aberrant oncogene expression, we probed Northern blots of UMR and other osteoblastic cells with a panel of oncogene probes. These blots, when probed with a cDNA specific for v-H-ras, revealed a 7.0-kilobase (kb) H-ras-related transcript (designated HRRT) in UMR 106-01 cells that was not expressed in other osteoblastic cells. Osteoblast-enriched calvarial cells expressed the typical 1.1-kb H-ras mRNA, which was absent in UMR cells. Additionally, Western blots of lysates of UMR cells documented the presence of three proteins immunologically related to H-rasp21. To determine whether HRRT represented a recombinant retrovirus product, Northern blots were probed with a cDNA specific for the highly conserved gag-pol region of Moloney murine leukemia virus. These blots showed parallel cross-reactivity with an apparently identical transcript of 7.0 kb. The 7.0-kb transcripts detected by both v-H-ras and gag-pol probes declined to the same extent after treatment with concentrations of PTH known to inhibit proliferation of these cells. PTH regulated the abundance of HRRT in a time- and dose-dependent manner, with greatest repression of the transcript after 8 h of treatment with 10(-8) M PTH. The decrease in HRRT could not be completely accounted for by changes in transcriptional activity, as determined by nuclear run-on assays.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of an H-ras-related transcript by parathyroid hormone in rat osteosarcoma cells. 135 1

Amplification and rearrangement of cellular proto-oncogenes are two of the several possible genetic alterations implicated in carcinogenesis and tumor progression. Although morphologically similar tumors may be heterogeneous at the level of the genome, some tumor types have shown relatively frequent and consistent abnormalities of specific oncogenes. In order to determine the frequency of oncogene amplification and rearrangement in several types of human sarcomas and to determine if histologically similar tumors have common genetic alterations, we analyzed 26 primary sarcomas by Southern hybridization. The oncogene probes utilized were N- and H-ras, sis, EGF-R (erb-B-1), neu (erb-B-2), fos, N- and c-myc, mos, and yes. The tumors studied included: five rhabdomyosarcomas (one alveolar, four embryonal), six malignant fibrous histiocytomas, six leiomyosarcomas, four liposarcomas, two Ewing's sarcomas, one osteosarcoma, and two fibrosarcomas. Oncogene abnormalities were identified in three tumors. One rhabdomyosarcoma showed 12-fold amplification and concurrent rearrangement of sis. This particular tumor also revealed rearrangement of H-ras and 15-fold amplification of c-myc. A second rhabdomyosarcoma revealed rearrangement of neu. A liposarcoma had a sis rearrangement. These findings suggest that many sarcomas show no common structural oncogene abnormalities. The presence of differing oncogene alterations within the rhabdomyosarcoma group indicates genetic heterogeneity among histologically similar sarcomas. The finding of a sis rearrangement in both a liposarcoma and a rhabdomyosarcoma, however, may suggest common oncogenesis among different tumor types.
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PMID:Genomic alterations in sarcomas: a histologic correlative study with use of oncogene panels. 149 46

Here the adeno-associated virus Rep78 gene product was found to inhibit the expression of the chloramphenicol acetyltransferase and the bladder cancer-derived EJ-H-ras coding sequences when they were under the control of the natural cellular H-ras regulatory sequences. However, Rep78 had little or no effect on the expression of these same coding sequences when they were under the control of the regulatory sequences of the murine osteosarcoma virus long terminal repeat. These data indicate that the inhibition of H-ras by Rep78 depends upon sequences present within the cellular H-ras upstream regulatory region. Furthermore, these and earlier data indicate that Rep78 functions as an "antioncogene" or transformation suppressor gene, inhibiting H-ras as well as several viral oncogenes.
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PMID:Inhibition of H-ras expression by the adeno-associated virus Rep78 transformation suppressor gene product. 164 67

Canine and human osteosarcoma are very similar clinically, radiologically and pathologically. DNA extracted from canine osteosarcomas (n = 9) and normal canine control tissues (n = 17) was examined for amplification of the c-sis, c-myc, N-myc and c-H-ras protooncogenes. Statistically significant amplification of the c-sis and c-myc protooncogenes was evident in the tumor tissues as compared to the normal control tissues (P less than 0.05). DNA and total cellular RNA from cultured canine and human osteosarcoma and fibroblast cell lines were examined for amplification or enhanced expression of c-sis and c-myc. Very low levels of c-myc and c-sis DNA amplification were noted in canine osteosarcoma cells as compared to canine fibroblasts. Immunostaining of sections of human and canine osteosarcoma for the sis gene product, PDGF B, showed similar levels and patterns of expression in both populations of tumors.
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PMID:Low level amplification of c-sis and c-myc in a spontaneous osteosarcoma model. 220 81

A murine mRNA (provisionally called 2ar) is described whose abundance is greatly increased by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate both in JB6 epidermal cells in vitro and in epidermis in vivo. We have previously shown induction of 2ar in epidermal or fibroblast cell lines by tumor promoters, growth factors, and transformation with H-ras. The 2ar mRNA appears to be derived from a single copy gene. It encodes the mouse homolog of rat osteopontin, a 41.5-kDa glycosylated bone phosphoprotein that binds to fibroblasts and osteosarcoma cells and to hydroxylapatite (bone matrix). The rat and mouse sequences are 84% identical at the amino acid level and 87% identical at the nucleotide level. Many of the primary structural features are conserved, including a run of 9-10 aspartic residues and a Gly-Arg-Gly-Asp-Ser cell adhesion sequence. Antiserum raised against portions of the predicted polypeptide immunoprecipitated proteins of apparent Mr 55,000-70,000 both from reticulocyte lysates containing the translation products of hybrid-selected mRNA and from cell culture medium containing metabolically labeled proteins secreted by JB6 cells. The results presented here demonstrate that osteopontin is identical to a transformation-associated phosphoprotein whose level of expression by cultured cells and abundance in human sera has been correlated with tumorigenicity. These results suggest a role for osteopontin in carcinogenesis. The murine version of osteopontin has been given the formal name "secreted phosphoprotein 1" and the designation spp.
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PMID:Osteopontin, a transformation-associated cell adhesion phosphoprotein, is induced by 12-O-tetradecanoylphorbol 13-acetate in mouse epidermis. 272 55

The structures and transcripts of sixteen different cellular oncogenes (c-oncs) were studied in ten human osteosarcoma lines transplanted onto nude mice by Southern and Northern blot hybridization techniques. One osteosarcoma line (WAJI) had an amplification of c-myc gene at about ten-fold normal amount. High levels of c-myc transcripts were detected in four (MINO, OZA, SU, KiKu) of ten osteosarcoma lines. High levels of c-H-ras transcripts were also detected in four (OZA, TOMO, WAJI, SU) of ten osteosarcoma lines. Gene transcripts of c-fos were detected in only one osteosarcoma line (WAJI). Osteosarcomas containing detectable c-myc transcripts grew more rapidly in nude mice than those with undetectable c-myc transcripts. Levels of c-H-ras transcripts were apparently unrelated to the tumor growth rate.
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PMID:[Analysis of cellular oncogenes in human osteosarcomas transplanted into nude mice]. 316 47

Human herpesvirus 6 strain U1102 (HHV-6A) was shown to contain a 1,473-bp functional transformation suppressor gene (ts). ts exhibited 24% identity and 51% similarity to adeno-associated virus type 2 Rep68/78. Like adeno-associated virus type 2 Rep68/78, HHV-6A ts suppressed H-ras transformation of NIH 3T3 cells. Suppression of H-ras transformation was eliminated by translation termination linker mutation at amino acid 25, 125, or 245. These data indicated the importance of the C-terminal portion of the ts protein. H-ras transformation was suppressed by ts only when H-ras was expressed by its endogenous H-ras promoter and not when it was expressed by the heterologous murine osteosarcoma virus long terminal repeat (LTR). Furthermore, ts suppressed chloramphenicol acetyltransferase (CAT) activity when the CAT gene was expressed from the H-ras promoter but not the murine osteosarcoma virus LTR promoter. Taken together, the data showed that ts suppressed H-ras transformation at the level of the H-ras promoter. To further identify the interaction of ts with transcriptional regulatory elements, the human immunodeficiency virus type 1 (HIV-1) LTR was used. This promoter was selected because it has well-defined transcriptional regulatory elements for both basal and activated transcription, because its activity is inhibited by the Rep68/78 gene, and because both HHV-6 and HIV-1 naturally infect CD4+ T cells in vivo and have been shown to infect the same cell in vitro. ts suppressed expression from both wild-type and upstream mutant HIV-1 LTR-CAT constructs. However, downstream HIV-1 TAR mutations reversed ts suppression, indicating that TAR is one of the critical elements involved. The data presented demonstrated that HHV-6A ts functionally suppressed H-ras transformation and HIV-1 LTR expression and thus that it may be useful in future gene therapy.
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PMID:Human herpesvirus 6A ts suppresses both transformation by H-ras and transcription by the H-ras and human immunodeficiency virus type 1 promoters. 760 62

The ras oncogene family has been implicated in tumor resistance to ionizing radiotherapy. Using the gene-transfer model, we show here that ras expression may also affect cell responses to chemical inducers of oxidative stress. Studies involving human osteosarcoma subclones, which vary in their levels of EJras expression, revealed a tight correlation between the amounts of ras-encoded mRNA and p21 produced, and the degree of resistance to doxorubicin or hydrogen peroxide. Differences in response could not be explained by increased activity of anti-oxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione S-transferase or glutathione peroxidase. Moreover, there were no significant differences in glutathione levels. Although the resistant cells had elevated levels of gamma-glutamyl-transferase mRNA indicative of an increased rate of glutathione turnover, this elevation was not specific for ras-transfected cell lines. Lovastatin, an inhibitor of protein isoprenylation critical for p21ras membrane association and function, restored the sensitivity of ras-transformed cells to doxorubicin and hydrogen peroxide. The data indicate that pharmacological agents affecting ras expression may enhance responses of some human tumors to free-radical-mediated chemotherapies.
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PMID:Tumor resistance to oxidative stress: association with ras oncogene expression and reversal by lovastatin, an inhibitor of p21ras isoprenylation. 782 24

Expression of ras has been correlated with increased intrinsic resistance to ionizing radiation. In this study we show that increased EJras expression in human cells is associated with a decrease in the frequency of radiation-induced micronuclei. The experimental system consisted of human osteosarcoma-derived cell lines which quantitatively vary in their EJras expression. There was a dose-dependent relationship between radiation dose and micronuclei formation in all cell lines tested. Human osteosarcoma cells, in which the ras level was undetectable, had the highest frequency of micronuclei production at all radiation doses tested. At 4 Gy the most radioresistant cells exhibited a 41.5 +/- 5% decrease in the production of micronuclei concomitant with high ras expression in comparison with the relatively radiosensitive parental cell line. Cells expressing a low amount of EJras demonstrated a 23 +/- 3% decrease in micronuclei induction compared with parental cells. Treatment of cells with lovastatin, an inhibitor of ras-encoded p21ras post-translational processing via the mevalonate pathway, markedly decreased the yield of micronuclei formation in cells transfected with ras; the drug had no effect on radiation-induced micronuclei formation in parental cells. The use of the in vitro micronuclei assay has provided a convenient way to visualize differences in the genotoxic damage induced by ionizing radiation in cells which express different amount of EJras. The results indicate that elevation of ras expression in human cells can lead to a decrease in the number of radiation-induced micronuclei formed and that this relationship is dependent on membrane association of ras-encoded p21.
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PMID:Differences in radiation-induced micronuclei yields of human cells: influence of ras gene expression and protein localization. 790 94

The large rep gene products (rep68 and rep78) of adeno-associated virus (AAV) are pleiotropic effector proteins which not only play a critical role in AAV DNA replication and in the trans-regulation of AAV promotor elements, but are also known for their onco-suppressive functions. We have previously demonstrated that the large AAV rep protein will strongly inhibit expression from the c-H-ras promoter, but not the murine osteosarcoma virus long terminal repeat (MSV-LTR) promoter. To investigate the possibility that rep may physically bind to these promoter sequences, specifically to GCTC motifs, we conducted electrophoretic mobility shift assays (EMSA) with a maltose binding protein-rep chimeric protein, MBP-rep68 delta, and synthetic double stranded DNA substrates of sequences selected from the c-H-ras and MSV-LTR promoters, as well as with the AAV TR. We find that MPB-rep68 delta bound the AAV TR DNA sequence (three motifs) most strongly, followed by the selected c-H-ras DNA sequence (two noninterfering motifs), and most poorly to the MSV-LTR DNA (one motif). These data are consistent with our previous study and suggest a direct mechanism of action for AAV rep inhibition of the c-H-ras promoter. Furthermore, the results suggest that the number of GCTC motifs, when closely associated, affect the affinity of rep binding. Finally, we find that MBP-rep68 delta also binds to the c-H-ras oligomer substrates which have secondary hairpin structures.
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PMID:The regulatory rep protein of adeno-associated virus binds to sequences within the c-H-ras promoter. 795 51


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