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 expression of both epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), and of their receptors (EGFR and PDGFR) was immunohistochemically examined in 37 cases of osteosarcoma. Furthermore, immunostaining for p53 protein and Ki-67 antigen by MIB-1 was carried out and compared with the above results. EGFR (81%) expressed more often than EGF (51%) and the expression of EGF and EGFR, and PDGF and PDGFR were recognized in 49% and 38%, respectively. In eleven cases (30%), the expression of both growth factors and their receptors was combined. Anaplastic osteosarcoma showed higher MIB-1 index than osteoblastic and fibroblastic subtypes (P < 0.05). High grade osteosarcomas (G3 and G4) revealed higher MIB-1 index compared with low grade tumors (G1 and G2). PDGF positive tumors (MIB-1 index: 20.0) showed significantly higher proliferation compared with PDGF negative tumors (MIB-1 index: 6.5) (P < 0.01). Five out of 37 cases (13.5%) showed positive immunoreaction for p53. There was no correlation of p53 status with MIB-1 index and the expression of growth factors or their receptors. Our results suggest that PDGF expression may be an important mediator of cell proliferation control, via an autocrine mechanism, in human osteosarcoma.
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PMID:Expression of growth factors and their receptors in human osteosarcomas. Immunohistochemical detection of epidermal growth factor, platelet-derived growth factor and their receptors: its correlation with proliferating activities and p53 expression. 854

We investigated the effects of the potent somatostatin analog RC-160 on the growth of human osteosarcoma cell lines SK-ES-1 and MNNG/HOS, transplanted into nude mice or cultured in vitro. Growth of SK-ES-1 and MNNG/HOS tumors in nude mice was significantly inhibited after 4 weeks of treatment with daily s.c. injections of 100 micrograms RC-160, as measured by a reduction in tumor volume and weight. Histologically, the number of mitotic cells was decreased in the groups treated with RC-160. In mice bearing either tumor model, administration of RC-160 significantly decreased serum growth hormone and insulin-like growth factor I (IGF-I) levels. Specific high-affinity receptors for somatostatin and epidermal growth factor were found on membranes of MNNG/HOS tumors but not on SK-ES-1 tumors. Receptor analyses also demonstrated high-affinity binding sites for IGF-I on membranes of both tumors. In cell cultures, the proliferation rate of MNNG/HOS cells, but not of SK-ES-1, was significantly suppressed by RC-160. Our findings demonstrate that RC-160 can significantly inhibit the growth of SK-ES-1 and MNNG/HOS osteosarcomas in mice.
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PMID:Somatostatin analog RC-160 inhibits the growth of human osteosarcomas in nude mice. 863 6

This study was designed to test the hypothesis that treatment of human bone cells with mitogenic concentrations of fluoride would lead to an increase in the steady state level of tyrosyl phosphorylation of specific cellular proteins. With an immunoblot assay method, it was found that mitogenic concentrations of fluoride (i.e. 50-200 mumol/L) induced a dose- and time-dependent increase in the level of tyrosyl phosphorylation of at least 13 cellular proteins in both normal human bone cells and human TE85 osteosarcoma cells. Time-course studies revealed that a statistically significant increase in tyrosyl phosphorylation of these 13 cellular proteins in human bone cells was observed after 3-6 h of fluoride treatment and was sustained for up to 24 h. This time course was not compatible with a direct activation of tyrosyl kinases, as epidermal growth factor, which activates tyrosyl kinase activity, induced an immediate and acute response that was rapidly reversible within 1 h. Although fluoride increased the steady state tyrosyl phosphorylation of the cellular proteins in human bone cells, the same micromolar doses of fluoride had no effect on human skin fibroblasts, which are fluoride-nonresponsive cells. The effects of fluoride were rapidly reversible in the absence of fluoride and could be acutely potentiated by pretreatment with epidermal growth factor. In summary, we have shown for the first time that mitogenic concentrations (i.e. 50-200 mumol/L) of fluoride increased the steady state level of tyrosyl phosphorylation of at least 13 cellular proteins in human bone cells, and that the increases were relatively show in onset and sustained. In conclusion, these findings are consistent with the hypothesis that the osteogenic actions of fluoride are mediated at least in part by an inhibition of the activity of one or more fluoride-sensitive phosphotyrosyl protein phosphatases in human bone cells.
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PMID:Fluoride at mitogenic concentrations increases the steady state phosphotyrosyl phosphorylation level of cellular proteins in human bone cells. 867 80

The gene encoding PTH-related peptide (PTHrP), a protein that plays a primary role in the development of humoral hypercalcemia of malignancy, is widely expressed in normal and neoplastic tissues. This study demonstrates that expression of the PTHrP gene has features of early response genes, including up-regulation after serum repletion of serum-starved ROS 17/2.8 (rat osteosarcoma) cells. The PTHrP messenger RNA (mRNA) levels were induced within 30 min and peaked at 4 h. Elevated mRNA levels were accompanied by an increase in secreted PTHrP. The serum effects on PTHrP mRNA levels were blocked by actinomycin D, suggesting a requirement for gene transcription. Nuclear run-on assays revealed a 3-fold increase in PTHrP gene transcription 4 h after exposure to serum. Deletions of the 5' flanking sequence of the rat PTHrP gene fused to the chloramphenicol acetyltransferase gene and transfected into ROS 17/2.8 cells showed that the serum-responsive region is located between -1.05 kb and -0.3 kb upstream of the transcription start site. PTHrP mRNA levels were also induced by cycloheximide, another feature common to early response genes. The PTHrP mRNA half-life in serum-starved cells was 56 min. Serum treatment prolonged the half-life 2.7-fold, suggesting serum-induced stabilization of the mRNA. Insulin and epidermal growth factor also induced PTHrP mRNA expression in a time-dependent manner analogous to serum, indicating that the effects of serum may be mediated, at least partially, through these agents. In summary, serum up-regulated PTHrP mRNA expression through both transcriptional and posttranscriptional mechanisms. This rapid stimulation by growth factors suggests that PTHrP may contribute to the early cellular response after growth factor stimulation.
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PMID:Serum stimulation of parathyroid hormone-related peptide gene expression in ROS 17/2.8 osteosarcoma cells through transcriptional and posttranscriptional mechanisms. 875 33

GH induces phosphorylation of a number of cellular proteins, of which several have now been identified, such as mitogen-activated protein kinase, insulin receptor substrate-1, and members of the JAK kinase and STAT families of proteins. However, other phosphorylated proteins remain unidentified. Growth factors and cytokines, including epidermal growth factor, insulin, pp60v-scr, and angiotensin II, induce a rapid phosphorylation of annexin I, a 35-kDa member of the annexin family of Ca2+ and phospholipid-binding proteins. The osteoblast-like rat osteosarcoma cell-line UMR-106.01, in which GH acts as a mitogen via a high affinity GH receptor, was used as a model for GH-induced protein phosphorylation. It is demonstrated by immunoblotting and immunoprecipitation techniques that GH induces the phosphorylation of annexin I on tyrosine residues. This phosphorylation is dose and time dependent. Induction of annexin I phosphorylation is delayed compared with that of JAK2. These results identify annexin I as a protein that becomes tyrosine phosphorylated under the influence of GH and show that phosphorylation of annexin I is a general phenomenon that follows activation of a cell by hormones or cytokines.
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PMID:Growth hormone induces tyrosine phosphorylation of annexin I in rat osteosarcoma cells. 882 96

1Alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is a potent mediator of differentiation and maintenance of specific functions of osteoblasts. To detect novel targets for 1,25-(OH)2D3 action, we applied differential display PCR to human fetal osteoblast-like cells and identified the human analog of murine cystein rich protein 61 (hCYR61) as a 1,25-(OH)2D3-responsive immediate early gene in differentiated fetal osteoblast-like cells. The murine gene CYR61 is important for cell-cell and cell-matrix interactions, and it belongs to an emerging gene family of cysteine-rich proteins. hCYR61 messenger RNA (mRNA) steady-state levels were stimulated 11-fold by 10 nM 1,25-(OH)2D3 by 1 h and declined to control levels by 4 h. This transient stimulation of hCYR61 mRNA was not inhibited by cycloheximide but was prevented by actinomycin D, indicating that the 1,25-(OH)2D3 effect involves transcriptional events and does not require de novo protein synthesis. hCYR61 mRNA stability was not influenced by 1,25(OH)2D3, whereas cycloheximide treatment stabilized hCYR61 mRNA. FCS, as well as growth factors and cytokines such as basic fibroblast growth factor, epidermal growth factor, tumor necrosis factor alpha, and interleukin-1, strongly elevated hCYR61 mRNA steady-state levels within 1 h. hCYR61 mRNA was expressed also in primary human osteoblasts and osteosarcoma cell lines. Using a commercial tissue blot, hCYR61 mRNA was only observed in skeletal muscle. The fast and transient response of hCYR 61 to 1,25-(OH)2D3, serum, growth factors, and cytokines suggests an important role of hCYR61 for osteoblast function and differentiation.
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PMID:The human analog of murine cystein rich protein 61 [correction of 16] is a 1alpha,25-dihydroxyvitamin D3 responsive immediate early gene in human fetal osteoblasts: regulation by cytokines, growth factors, and serum. 952 60

The paper analyzes the data of long-term studies made in the N. N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences. The study dealt with androgen exchange, the baseline levels of serum sexual steroid hormones and their receptors in the tumor, the blood concentrations of the sexual steroids conjugated globulin and pituitary hormone, the metabolism of arachidonic acid, the expression of epidermal growth factor and its ligands, the amount of calmodulin, cAMP in the osteogenic sarcoma in 300 patients aged 14-56 years. Analyzing the findings suggests that there are some directions in studies, development, and practical introduction of new pathogenetic therapies of osteosarcoma, which are associated with the regulation of androgen exchange, the correction of the cyclooxygenase pathway of arachidonic acid, expression of receptors of epidermal growth factor and its ligands in the tumor.
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PMID:[Hormones and auto-paracrine tumor growth regulators in osteogenic sarcoma]. 998 64

Herein we describe the cDNA sequence of a novel human gene, ITGBL1, encoding a beta integrin-related protein termed TIED [for ten beta integrin epidermal growth factor (EGF)-like repeat domains]. Overlapping cDNA clones from fetal lung, HUVEC, and osteoblast cDNA libraries encode a sequence comprising a typical signal peptide, followed by a hydrophilic 471-amino-acid domain containing 10 tandem EGF-like repeats strikingly similar to those found in the cysteine-rich "stalk-like" structure of integrin beta subunits. The EGF-like repeats of TIED and beta integrins are unique in that they alternate in homology and possess two additional cysteines (eight in total) whose positions differ from those in the other eight-cysteine EGF-like domains of laminin, fibrillin, and the latent TGF-beta binding proteins. TIED mRNA transcripts of 2.8 kb were detected in aorta, thymus, and osteogenic sarcoma cells. The ITGBL1 gene was mapped to human chromosome 13, band 13q33. We suggest that ITGBL1 may be linked in some way with the evolution of the integrin beta subunits.
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PMID:Cloning and characterization of a novel beta integrin-related cDNA coding for the protein TIED ("ten beta integrin EGF-like repeat domains") that maps to chromosome band 13q33: A divergent stand-alone integrin stalk structure. 1005 2

To evaluate the mechanisms by which epidermal growth factor (EGF) regulates actin-based cellular processes such as cell migration, we first examined the effects of EGF on cell adhesion, which is essential for cell migration. In mouse B82L fibroblasts transfected with the full-length EGF receptor, EGF promotes cell rounding and attenuates cell spreading on fibronectin, laminin, and vitronectin, and thus appears to reduce the strength of cell adhesion. Moreover, EGF synergizes with multiple extracellular matrix (ECM) components in the promotion of integrin-mediated cell migration of several different cell types, including fibroblasts and various carcinoma and osteosarcoma cell lines. Interestingly, co-presentation (co-positioning) of EGF with laminin or fibronectin is essential for EGF-stimulated migration. When EGF is mixed with the cells instead of the ECM components, it has little effect on cell migration. These results suggest that co-presentation of EGF with ECM components can enhance the polarization events required for directional cell movement. To identify the EGF receptor elements critical for the EGF stimulation of cell migration, B82L fibroblasts were transfected with either mutated or wild-type EGF receptors. Surprisingly, we found that B82L-Parental cells that lack the EGF receptor are not able to migrate to fibronectin, even though they can adhere to fibronectin. However, the introduction of wild-type EGF receptors into these fibroblasts enables them to migrate toward fibronectin even in the absence of EGF. The requirement of the EGF receptor for cell migration does not appear to result from the secretion of EGF or TGF-alpha by the cells transfected with the EGF receptor. Furthermore, cells expressing EGF receptors that are kinase-inactive, or C-terminally truncated, exhibit little migration toward fibronectin, indicating that an intact EGF receptor kinase is required for fibronectin-induced cell migration. In addition, neutralizing anti-EGF receptor antibodies attenuate cell migration in the presence of EGF, and inhibit migration to fibronectin or laminin alone. These results further suggest that the EGF receptor is downstream of integrin activation in the signal transduction pathways leading to fibroblast migration.
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PMID:Integrin-mediated migration of murine B82L fibroblasts is dependent on the expression of an intact epidermal growth factor receptor. 1019 8

It has been previously observed that the transforming growth factor beta3 (TGFbeta3) gene can be activated by both estradiol (E(2)) and selective estrogen receptor modulators (SERMs) in vivo but that only SERMs have a potent stimulatory effect on the TGFbeta3 promoter in cultured cells. We demonstrate in this report that E(2) can act also as a potent inducer of the TGFbeta3 promoter via a novel and specific estrogen receptor (ER)alpha-mediated mechanism. Our results show that treatment with epidermal growth factor or transfection of a constitutively active Ras mutant allows E(2) to induce the TGFbeta3 promoter via ERalpha in cotransfected HeLa and osteosarcoma MG63 cells. Both protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) inhibitors can block the combined stimulatory effect of E(2) and epidermal growth factor/Ras. However, E(2) induction of the TGFbeta3 promoter was found to be unaffected by mutation of ERalpha serine 118, a well-characterized target of MAPK. Progressive deletion analysis of the ERalpha amino-terminal region delineated three separate domains modulating the E(2)/activated Ras response, revealing a complex functional organization of the ERalpha A/B domain required for regulation of the TGFbeta3 promoter. In addition, PKC and MAPK inhibitors had no effect on the induction of TGFbeta3 promoter activity by the SERM EM-652. These results indicate that induction of the TGFbeta3 promoter by the E(2)/ERalpha complex requires the concomitant activation of PKC and MAPK signaling and provide a novel framework for the design of more effective estrogen-based therapeutic strategies.
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PMID:Requirement of Ras-dependent pathways for activation of the transforming growth factor beta3 promoter by estradiol. 1115 47


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