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)

U-2 human osteosarcoma cells secrete a 29/32/34 kilodalton (kDa) insulin-like growth factor binding protein (IGFBP) identified as O-glycosylated IGFBP-5. Treatment of U-2 cells with IGF-I markedly increased medium levels of IGFBP-5 in a concentration- and time-dependent manner; other skeletal regulatory factors (GH, insulin, PTH, dexamethasone, beta-estradiol, 1,25-dihydroxyvitamin D3, transforming growth factor-beta) had no effect. IGF-I increased IGFBP-5 levels in the culture medium 10-fold without influencing IGFBP-5 messenger RNA abundance. IGF-I, IGF-II, and the IGF-I analog [1-27Gly(4)38-70] IGF-I bound IGFBP-5 with high affinity and, when added to U-2 cultures, effectively promoted IGFBP-5 accumulation in the medium. On the other hand, des(1-3)IGF-I and [QAYL]IGF-I, IGF-I analogs that did not bind IGFBP-5, failed to elicit an increase in medium IGFBP-5. Cell-free incubation of recombinant human (rh) IGFBP-5 in U-2 conditioned medium resulted in a marked reduction of detectable rhIGFBP-5; the presence of IGF-I or IGF-II peptide partially prevented this decrease. By immunoblot analysis, loss of intact rhIGFBP-5 (29-kDa unreduced, 34-kDa reduced) coincided with the appearance of a 16-kDa proteolytic fragment. U-2 conditioned medium contained immunoreactive IGFBP-5 at 29-34-kDa, 20-kDa, 17-kDa, and 16-kDa. Endogenous IGFBP-5 inhibited IGF-I but not des(1-3)IGF-I-stimulated U-2 cell proliferation. In conclusion, IGF peptides can regulate the availability of IGFBP-5 in osteoblast-like cells by impeding IGFBP-5 proteolysis. The biological consequence of increased medium IGFBP-5 appears to be decreased cell responsiveness to IGF-I stimulation.
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PMID:Regulation and biological effect of endogenous insulin-like growth factor binding protein-5 in human osteoblastic cells. 768 91

Transforming growth factor-beta modulates the proliferation, differentiation, and synthetic activity of osteoblasts, but its mechanisms of action are not fully understood. Because ascorbate also influences osteoblast differentiation and is a cofactor for collagen synthesis, the present study examined the effect of transforming growth factor-beta on the initial rate of transport and steady-state concentration of ascorbate in an osteoblastic cell line. UMR-106 rat osteosarcoma cells accumulated reduced vitamin C from culture medium. Virtually all accumulation of ascorbate was accomplished by a saturable Na(+)-dependent transport mechanism. Transforming growth factor-beta increased the initial rate of ascorbate transport, measured in either attached or suspended cells. Within 24 h, the growth factor also increased the steady-state intracellular concentration of ascorbate, without significantly changing cell volume or the DNA or protein content of cultures. These data provide evidence that Na(+)-ascorbate cotransport activity controls ascorbate concentration in osteoblasts. Furthermore, the results indicate that both the transport rate and steady-state concentration of ascorbate in these cells are regulated by transforming growth factor-beta.
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PMID:Ascorbate concentration in osteoblastic cells is elevated by transforming growth factor-beta. 773 53

We investigated the contribution of c-fos protooncogene in the mitogenic effect of transforming growth factor-beta (TGF beta) in serum-deprived, confluent rat calvaria osteoblastic cells. The TGF beta-induced growth in these cells was associated with an immediate and transient c-fos mRNA accumulation, similar to the inductive effect of fetal calf serum. To assess the role of c-fos in the response to TGF beta, we used a c-fos antisense (AS) oligonucleotide displaying duplex formation with rat c-fos mRNA. Studies of AS and sense (S) uptake by osteoblastic cells demonstrated that incorporation of labeled oligomers was maximal at 2 h, and the incorporated AS oligonucleotide remained intact for 24 h. Immunofluorescence analysis of c-Fos-labeled cells demonstrated that AS, but not S, oligonucleotide reduced c-Fos protein expression, suggesting specific efficient inhibition of c-fos translation by the AS oligomer. Proliferation assays showed that cell growth induced by fetal calf serum was inhibited by the AS, but not by the S oligonucleotide, in both normal rat osteoblasts and ROS 17/2.8 osteosarcoma cells, demonstrating efficient and specific blockage of cell growth by the AS oligomer. The mitogenic effect of TGF-beta was abolished in cells cultured in the presence of AS, whereas S had no effect, showing that c-fos is required for TGF beta-induced osteoblast cell growth. The results show that the induction of c-fos is implicated in the mitogenic effect of TGF beta in osteoblastic cells and provide a cellular mechanism involved in the response of these cells to TGF beta.
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PMID:c-fos protooncogene is involved in the mitogenic effect of transforming growth factor-beta in osteoblastic cells. 777 69

We investigated the role of protein kinase C (PKC) in osteoblast function using a set of putative PKC modulating factors and an in situ peptide substrate-based kinase assay in different types of osteoblastic cells. Primary calvarial rat osteoblastic cells (ROB) and ROS 17/2.8 osteosarcoma cells showed an equally high PKC activity when a maximal dose of PKC-activating phorbol ester was applied. The osteosarcoma cell line UMR 106-01 showed only 5-10% of this maximal PKC activity. All 3 cell types responded to 10 U/ml thrombin with a 2-fold stimulation of PKC activity. However, no distinct direct effects of parathyroid hormone (bPTH (1-34)) or transforming growth factor-beta 2 (TGF-beta 2) were found in either of the cell types. The thrombin-induced stimulation of PKC was associated with an increase in the PTH-mediated cAMP response of ROB. Down-regulation of PKC-activity was found when ROB were treated for 24 h with phorbol ester and, interestingly, also after a 24 h treatment with bPTH (1-34) and TGF-beta 2. We conclude that differences in PKC activity exist among osteoblastic cell types, which may be related to their different proliferative activity. Direct PKC activation may lead to modulation of the cAMP signaling pathway. Down-regulation of PKC activity by bPTH (1-34) and TGF-beta 2 provides an interesting possible mechanism for the long-term regulation of signal transduction.
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PMID:Regulation of protein kinase C activity by phorbol ester, thrombin, parathyroid hormone and transforming growth factor-beta 2 in different types of osteoblastic cells. 799 86

The expression of the core proteins and the co-polymeric structure of the glycosaminoglycan chains of three different small proteoglycans (biglycan, decorin, proteoglycan-100) have been examined in the human osteosarcoma cell line MG-63. The three proteoglycans, which are carrying either one or two chondroitin/dermatan sulphate chains, were synthesized in a similar molar ratio, as determined by [35S]methionine as well as by [35S]sulphate incorporation. After sulphate ester formation, they were secreted into the culture medium with similar kinetics. Immune staining with monospecific antibodies revealed that at least biglycan and proteoglycan-100 were present in all individual cells. However, in contrast to these similarities, the glycosaminoglycan moiety of proteoglycan-100 was composed exclusively of chondroitin 4- and 6-sulphate repeating units, whereas biglycan and decorin contained hybrid polymers of chondroitin and dermatan sulphate with approximately 90% 4-sulphated disaccharide repeating units. Treatment with transforming growth factor-beta resulted in a marked down-regulation of proteoglycan-100 synthesis without significant alteration of its glycosaminoglycan structure. Up-regulation of biglycan and moderate down-regulation of decorin were accompanied by a small decrease in the conversion of chondroitin to dermatan sulphate disaccharide units in both cases. The specific stimulation of the biosynthesis of proteoglycan-100 by tumour necrosis factor-alpha was without consequence for its glycosaminoglycan composition. Treatment with tumour necrosis factor-alpha had no influence on the synthesis and glycosaminoglycan structure of biglycan and decorin. These findings support the proposal of the importance of the core protein for the determination of the extent of glycosaminoglycan modification.
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PMID:Different galactosaminoglycan composition of small proteoglycans from osteosarcoma cells. 813 Mar 87

Decorin is a leucine-rich, chondroitin/dermatan sulfate proteoglycan which binds collagen and growth factors. We have recently completed the genomic organization of human decorin and discovered two alternatively spliced leader exons, designated exon Ia and Ib, in the 5'-untranslated region. Initial analysis of the sequences upstream to these two exons showed that promoter Ia contained only two GC boxes while promoter Ib contained a CAAT and two TATA boxes in close proximity to the transcription start site. To determine if these 5'-flanking sequences exhibited promoter activity, chimeric chloramphenicol acetyltransferase expression plasmids containing the promoter region of either exon Ia or Ib were transfected into HeLa and MG-63 osteosarcoma cells. The results showed that only the region flanking exon Ib was functional. In vitro transcription assay generated two transcripts of 92 and 82 base pairs (bp) indicating that both TATA boxes could be used. Using stepwise 5' deletion analysis we found that the minimum promoter region at -140 bp from the transcription start site, which contained only the CAAT and the two TATA boxes, exhibited strong promoter activity. When a larger construct containing an additional 800 bp of upstream region was tested, a significant increase in transcriptional activity was observed. Interestingly, this promoter region contained several putative binding sites for ubiquitous factors (AP1, AP5, and NF-kappa B) and for transforming growth factor-beta and a 150-bp homopurine/homopyrimidine element with several mirror repeats. When contained in a supercoiled plasmid, this sequence exhibited sensitivity to endonuclease S1, an enzyme that preferentially digests single-stranded DNA. Precise S1 mapping, obtained by direct sequencing of nine distinct S1-generated clones, revealed that in all cases the borders of the sensitive sequence resided within the pur/pyr segment. We propose that this region of the promoter could adopt an intramolecular hairpin triplex structure in vivo and may play a role in the chromatin organization at the decorin gene locus. In addition, this region was able to up-regulate a minimal heterologous promoter in transient transfection assays. The results show that the structure of the decorin gene promoter is different from that of any other proteoglycan promoter characterized so far and indicate that the pur/pyr segment plays a role in the regulation of gene transcription.
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PMID:Structural and functional characterization of the human decorin gene promoter. A homopurine-homopyrimidine S1 nuclease-sensitive region is involved in transcriptional control. 827 54

Parathyroid hormone-related peptide (PTHrP) was originally isolated from tumors associated with the development of hypercalcemia in vivo. Analyses of PTHrP gene expression have demonstrated that PTHrP is also produced in a wide variety of normal fetal and adult nonneoplastic tissues. The results of recent experiments have demonstrated that PTHrP is a growth factor-regulated gene, and different molecular forms of synthetic PTHrP display variable activities in assays for growth factor-like properties in vitro. We have studied the growth factor-like activity of PTHrP in cells transfected with a human PTHrP (hPTHrP) expression vector. Transfected cell lines contained increased amounts of PTHrP mRNA transcripts as assessed by Northern blot analysis. The PTHrP mRNA transcripts were translated into immunoreactive hPTHrP as measured by radioimmunoassay, and conditioned medium from transfected cell lines stimulated cyclic AMP (cAMP) formation in ROS 17/2.8 osteosarcoma cells. The transforming growth factor-beta-like properties of hPTHrP-producing NRK 49F clones were examined using the large-colony transformation assay in soft agar. PTHrP-producing NRK 49F clones did not form large colonies in the presence of epidermal growth factor. In contrast, PTHrP-producing and wild-type NRK 49F cells formed large colonies in the presence of epidermal growth factor and transforming growth factor-beta. No effect on cell growth was observed in PTHrP-producing NRK 49F rat kidney fibroblasts or mouse NIH 3T3 fibroblasts. In contrast, RCB 2.2 osteoblast cells expressing the hPTHrP cDNA were growth inhibited. Incubation of wild-type RCB 2.2 cells with synthetic hPTHrP[1-34] (at concentrations of 1.0-10.0 nM) also produced growth inhibition. PTHrP increased cAMP formation in RCB 2.2 cells but not in NIH 3T3 or NRK 49F cells. Incubation of RCB 2.2 cells with dibutyryl cAMP was also associated with inhibition of cell growth. The results of these studies demonstrate that PTHrP may function as an autocrine growth inhibitor of specific cell types, possibly through a cAMP-dependent pathway.
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PMID:Growth factor-like properties of parathyroid hormone-related peptide in transfected rodent cell line. 831 5

A protein fraction capable of eliciting cartilage or bone formation in vivo was purified more than 100,000-fold from a murine osteosarcoma (Dunn type). Intramuscular implantation of as little as 20 ng of the purified protein with 2 mg of pure skin collagen consistently induced ectopic new bone formation. The apparent molecular size of the purified protein was 32 kd on sodium dodecylsulfate-polyacrylamide gel electrophoresis. On reduction, the 32-kd protein split into subunits with the same partial amino acid sequences, and these partial sequences were identical to those of human bone morphogenetic protein-2B (BMP-4) which is assumed to be a member of the transforming growth factor-beta superfamily.
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PMID:Purification and characterization of a bone-inducing protein from a murine osteosarcoma (Dunn type). 851 28

Prostate tumor cells preferentially metastasize to bony sites and lymph nodes at a frequency in excess of that which would be predicted by random tumor cell dissemination. In order to determine whether chemoattractants in these organs promote organ-specific metastasis, we utilized human cell lines derived from and/or related to these organs as sources of potential chemoattractants. Secretory proteins derived from the cell lines MG-63 (osteosarcoma), SK-ES-1 (Ewing's sarcoma), and KG-1 (leukemia) stimulated chemomigration of the TSU-pr1 prostate tumor cells in a dose-dependent manner in Boyden chambers. In addition, secretory proteins from a human prostatic stromal cell line (hPS) and from the TSU-Pr1 prostate tumor cell line were also able to stimulate chemomigration of the TSU-pr1 cells through Boyden chambers. Since lymph nodes and bony sites represent organs of hematopoietic/lymphoid proliferation and activation, we undertook identification of specific cytokines present at these sites which may promote the chemomigration of prostate tumor cells. In this context, the cytokines interleukin-1 alpha, interleukin-2, interleukin-6, tumor necrosis factor-beta, transforming growth factor-beta, interferon alpha 2-a, and granulocyte-macrophage colony-stimulating factor did not stimulate chemomigration of the TSU-pr1 prostate tumor cell line. In contrast, the cytokine epidermal growth factor (EGF) stimulated chemomigration of the TSU-pr1 prostate tumor cells through the Boyden chambers in a dose-dependent manner. Western blot analysis of secretory proteins from the cell lines KG-1, SK-ES-1, MG-63, hPS, and TSU-pr1 identified EGF-immunoreactive proteins in all cases. In addition, EGF immunoreactivity was localized to the stroma of the human prostate, the osteogenic stroma of pelvic medullary bone, and the stroma within the capsule and trabeculae of pelvic lymph nodes. Hence, these results demonstrate that the cytokine EGF promotes the chemomigration of the TSU-pr1 prostate tumor cell line, and that EGF within the stroma of pelvic lymph nodes and medullary bone may act as a chemoattractant for prostate tumor cells, thereby facilitating the preferential formation of metastatic foci within these organs.
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PMID:Epidermal growth factor (EGF) promotes chemomigration of a human prostate tumor cell line, and EGF immunoreactive proteins are present at sites of metastasis in the stroma of lymph nodes and medullary bone. 854 75

mac25, a retinoic acid-inducible gene that is expressed at high levels in senescent epithelial cells, was initially cloned as a gene that is differentially expressed in meningioma. Although the homology of its product with members of family of insulin-like growth factor-binding proteins was suggested, the product also exhibits strong homology to follistatin, an activin-binding protein. However, a domain corresponding to the carboxyl terminus of follistatin is not found in mac25. The carboxyl-terminally truncated form of follistatin, generated by alternative splicing, has stronger activin-binding activity than the complete form. This result suggests that mac25 might act as an activated follistatin. Clonal growth of a p53-deficient osteosarcoma cell line was strongly inhibited when the murine mac25 gene, as well as the p53 gene, was introduced. Resembling activins that belong to the transforming growth factor-beta (TGF-beta) superfamily, mac25 and p53 might associate with similar but distinct targets, namely cyclin-dependent kinase inhibitors. However, there is no evidence for compensation of p53 function by mac25 in the development of p53-deficient mice, as judged from the pattern of expression of mac25 in mice. mac25 might act as a tumor suppressor, modulating signaling of the TGF-beta family, as does alpha-inhibin.
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PMID:A follistatin-like gene, mac25, may act as a growth suppressor of osteosarcoma cells. 864 39


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