Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In a previous study, we demonstrated that parathyroid hormone (PTH) inhibits mitogen-activated protein (MAP) kinase activation in osteosarcoma cells via a protein kinase A-dependent pathway. Here, we show that PTH can induce a transient activation of MAP kinase as well. This was observed in both Chinese hamster ovary R15 cells stably expressing high levels of rat PTH/PTH-related peptide receptor and parietal yolk sac carcinoma cells expressing the receptor endogenously. PTH was a strong activator of adenylate cyclase and phospholipase C in Chinese hamster ovary R15 cells. PTH-induced MAP kinase activation did not depend on activation of Gi, phorbol ester-sensitive protein kinase C, elevated intracellular calcium levels, or release of Gbetagamma subunits. It could, however, be mimicked by addition of forskolin or 8-bromo-cAMP to these cells. Prolonged treatment with forskolin caused sustained protein kinase A activity, whereas MAP kinase activity returned to basal levels. Subsequent treatment with PTH or 8-bromo-cAMP did not result in MAP kinase activation, whereas phorbol ester- or insulin-induced MAP kinase activation was unaffected. Finally, expression of a dominant negative form of Ras (RasAsn-17), which completely blocked insulin-induced MAP kinase activation, did not affect activation by PTH or cAMP. In conclusion, PTH regulates MAP kinase activity in a cell type-specific fashion. The activation of MAP kinase by PTH is mediated by cAMP and independent of Ras.
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PMID:Parathyroid hormone activates mitogen-activated protein kinase via a cAMP-mediated pathway independent of Ras. 901 86

We describe a premature aging disorder in a 15-year-old girl with severe growth and developmental deficiency. Her clinical findings included osteosarcoma, nuclear and subcapsular cataracts, insulin-resistant diabetes mellitus, osteoporosis, epilepsy, foot ulcers, erythroid macrocytosis, and unusual facial appearance. Hyaluronic acid levels in serum and urine were normal. Cultured skin fibroblasts had a normal potential for in vitro growth. This finding represents a new and unique premature aging syndrome.
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PMID:Premature aging syndrome with osteosarcoma, cataracts, diabetes mellitus, osteoporosis, erythroid macrocytosis, severe growth and developmental deficiency. 905 55

Insulin-like growth factor-1 (IGF-1) is a potent mitogen for osteoblasts. The primary signaling mechanism involved in mediating this proliferative effect of IGF-1 is not well defined. The roles of extracellular signal-regulated kinase 1 (ERK1) and cyclin-dependent kinase 2 (Cdk2) kinases in the IGF-1-induced proliferative signaling pathway of human osteosarcoma MG63 cells were investigated using a selective inhibitor of MEK, PD98059, and a Cdk inhibitor, olomoucine. Treatment of MG63 cells with PD98059 and olomoucine inhibited IGF-1-stimulated proliferation of these cells and induced cell cycle arrest at G0/G1. PD98059 significantly abolished IGF-1-stimulated kinase activity of ERK1 in a dose-dependent manner. PD98059 also inhibited the kinase activity of Cdk2 in IGF-1 stimulated cells, although the inhibition by olomoucine was much greater. The extent of inhibition of Cdk2 activity by PD98059 and olomoucine was consistent with their effects on cell proliferation and cell cycle. Cyclin A was complexed with Cdk2 in unstimulated MG63 cells, but Cdk2 kinase activity in the complex was up-regulated only in IGF-1-treated cells. This was consistent with an observed IGF-1-stimulated hyperphosphorylation of retinoblastoma protein (pRb) with the possibility that the activated Cdk2 kinase is involved in phosphorylation of pRb in IGF-1-induced cell proliferation. Taken together, these results suggest that the MEK/ERK pathway act in a positive regulatory fashion to activate Cdk2 in IGF-1-induced mitogenesis in osteoblasts.
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PMID:ERK pathway mediates the activation of Cdk2 in IGF-1-induced proliferation of human osteosarcoma MG-63 cells. 1023 73

Insulin-like growth factor-binding protein-5 (IGFBP-5) is produced by osteoblasts and potentiates insulin-like growth factor mitogenic stimulation in osteoblast cell cultures. Progesterone (PG) increased IGFBP-5 expression in normal human osteoblasts and increased IGFBP-5 transcription in U2 human osteosarcoma cells. We developed a chloramphenicol acetyltransferase reporter construct containing the human IGFBP-5 proximal promoter sequence, which includes TATA and CAAT boxes, and five putative PG response element half-sites. 10(-8) M PG increased promoter activity of this construct in U2 cells co-transfected with a PG receptor isoform A (PR(A)) expression vector. Analysis of 5' deletion constructs indicates that PG transactivation of IGFBP-5 promoter activity does not require the PG response element half-sites but does require the region -162 to -124 containing two tandem CACCC box sequences. Mutation of the proximal CACCC box at -139 eliminated PG transactivation. Gel shift assays using a -162 to -124 DNA fragment, U2 cell nuclear extracts, and purified PR(A) protein indicate that nuclear factors bind to a CACCC sequence at -139 and that PR(A) alters the pattern of transcription factor interaction with the CACCC sequence. Using a luciferase reporter construct containing base pairs -252 to +24 of the IGFBP-5 promoter, we found that both PR(A) and PR(B) isoforms mediated PG stimulation of promoter activity. These results suggest that PG may stimulate IGFBP-5 gene transcription via a novel mechanism involving PR and CACCC-binding factors.
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PMID:Progesterone stimulation of human insulin-like growth factor-binding protein-5 gene transcription in human osteoblasts is mediated by a CACCC sequence in the proximal promoter. 1047 2

A 6.5-year-old male with normal linear growth, despite septo-optic dysplasia, panhypopituitarism and a deficient GH/IGF axis, is presented. In addition to measuring IGF-I, IGF-II and IGFBP-3, serum IGFBP-1, -2, -4 and -5 were measured. A human osteosarcoma cell line was used to assess growth-promoting activity in the patient's serum. The role of leptin in linear growth in this case was investigated. There was no evidence for hyperinsulinism or hyperandrogenism. GH was undetectable upon multiple stimulation. GHBP was elevated. Serum IGF-I (25 microg/l), IGF-II (194 microg/l), IGFBP-3 (0.4 mg/l), and IGFBP-5 (87 microg/l) levels were low compared to age-matched prepubertal children. Serum IGFBP-4 level was normal. Molecular size of IGF-II in the patient's serum was normal, suggesting normal IGF-II bioavailability. Human osteosarcoma cell proliferation in response to the patient's serum was similar to sera from age-matched normal controls. Leptin levels were markedly elevated. Osteoblast cell proliferation was not stimulated by leptin. The data demonstrate that normal growth and osteoblast cell proliferation in this patient is not mediated by GH, total IGFs, insulin, or leptin, and suggest the presence of a yet unidentified growth factor or mechanism. The case offers a detailed picture of binding proteins in a case of growth without GH. It introduces osteoblast cell proliferation as a method of assessing serum growth-promoting activity in such cases. It adds IGF-II and leptin to the list of excluded growth-promoting candidates in GH-independent growth, and further demonstrates our incomplete understanding of the phenomenon of growth.
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PMID:Normal growth despite GH, IGF-I and IGF-II deficiency. 1051 93

Insulin-like growth factor (IGF) I is a potent mitogen for human osteosarcoma cells such as the Saos-2/B-10 cell line. IGF binding proteins (IGFBPs) prevent stimulation of DNA synthesis by IGFs. In contrast to recombinant human (rh) IGFBP-2, -3, -4, and -5, 10-100 nM rhIGFBP-6 stimulated [(3)H]thymidine incorporation into DNA and multiplication of Saos-2/B-10 cells. Upon withdrawal of serum, 30 nM IGFBP-6 also decreased apoptosis (within 4 h) and increased protein content and sodium-dependent phosphate uptake (within 24 h), but less potently than IGF I. (125)I-labeled rhIGFBP-6 did not bind to the cells, and cold IGFBP-6 did not affect (125)I-labeled IGF I binding. Production of IGF I, IGF II, and IGFBP-6 by the cells or significant degradation of rhIGFBP-6 could not be detected within 24 h of incubation. Thus, among the rhIGFBPs tested, rhIGFBP-6 is unique in stimulating osteosarcoma cell growth. Furthermore, it has an antiapoptotic effect.
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PMID:Mitogenic and antiapoptotic effects of insulin-like growth factor binding protein-6 in the human osteoblastic osteosarcoma cell line Saos-2/B-10. 1051 58

Insulin-like growth factor-I exerts potent mitogenic effects through the type I IGF receptor, a member of the insulin receptor family, and exhibits at the same time some insulin-like metabolic activities. We have questioned whether IGF-I presents moreover a modulatory effect upon programmed cell death (PCD)(apoptosis) in serum-deprived human osteosarcoma U-2 OS cells, a cell line synthesizing IGF-II and exhibiting an increased DNA synthesis following treatment with IGF-I. U-2 OS cells were cultured in a medium containing 0.8% FCS and growth arrest was induced by transfer to serum-free growth conditions. PCD was measured using a commercially available DNA degradation ELISA while viable cell numbers were counted microscopically after trypan exclusion to estimate net proliferative activity. Following serum withdrawal for 24 hrs., the level of PCD in U-2 OS cells was increased six-fold while cell number was reduced by approximately 35% compared to cells grown in the presence of 15% serum. Incubation with recombinant human IGF-I for 24 hrs. caused a dose-dependent inhibition of the level of programmed cell death. Co-incubation with an IGF-I receptor monoclonal antibody (alphaIR3) dose-dependently blocked the effects of 10 ng/ml IGF-I on PCD, with an ED50 of 1-10 ng/ml of alphaIR3 immunoglobulin. Conversely IGF-1 provoked a significant cell number increase, an effect blocked by addition of alphaIR3. The addition of an inhibitor of caspase 1 (ICE) had little effect on PCD but resulted in a net increase in the number of viable cells. In summary, IGF-I treatment of U-2 OS cells at the same time inhibits the induced programmed cell death and increases the cell number, effects which are blocked by addition of IGF-I receptor antibodies. These data support the hypothesis that IGF-I affects cells in a dual way, both by enhancing proliferative responses and by suppressing programmed cell death. The differential response between PCD and cell number to ICE inhibitors suggests the existence of independent control systems for these processes although the role of IGF-I in this study has yet to be determined.
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PMID:Insulin-like growth factor-I inhibits the progression of human U-2 OS osteosarcoma cells towards programmed cell death through interaction with the IGF-I receptor. 1072 73

The production of cysteine protease by two human osteosarcoma cell lines (MG-63 and SaOS2) was analyzed, as well as their modulation by interleukin 1beta (hIL-1 beta), interleukin 6 (hIL-6), insulin growth factor-1 (hIGF-1), oncostatin M (hOSM), leukemia inhibitory factor (hLIF) and growth hormone (hGH). Cysteine protease activities were detected using a synthetic substrate. The protease activities (especially cathepsin L activity) of both cell lines were increased significantly in the presence of hIL-1 beta, hIL-6 and hOSM. In contrast, hIGF-1 and hGH decreased these activities, and no effect was detectable in the presence of hLIF. The addition of antibodies against the gp-130 chain of the hIL-6 and hOSM receptors totally inhibited the stimulating effect of these two cytokines on cysteine protease activities. In increasing collagen type I degradation, hIL-1beta, hIL-6 and hOSM could be involved in bone resorption, whereas the inhibitory action of hIGF-1 and hGH on collagen type I degradation suggest that this factor could play a role in bone formation.
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PMID:Cysteine protease production by human osteosarcoma cells (MG63, SAOS2) and its modulation by soluble factors. 1085 75

In recent years, analogs of human insulin have been engineered with the aim of improving therapy for people with diabetes. To ensure that the safety profile of the human hormone is not compromised by the molecular modifications, the toxico-pharmacological properties of insulin analogs should be carefully monitored. In this study, we compared the insulin and IGF-I receptor binding properties and metabolic and mitogenic potencies of insulin aspart (B28Asp human insulin), insulin lispro (B28Lys,B29Pro human insulin), insulin glargine (A21Gly,B31Arg,B32Arg human insulin), insulin detemir (NN304) [B29Lys(epsilon-tetradecanoyl), desB30 human insulin], and reference insulin analogs. Receptor affinities were measured using purified human receptors, insulin receptor dissociation rates were determined using Chinese hamster ovary cells overexpressing the human insulin receptor, metabolic potencies were evaluated using primary mouse adipocytes, and mitogenic potencies were determined in human osteosarcoma cells. Metabolic potencies correlated well with insulin receptor affinities. Mitogenic potencies in general correlated better with IGF-I receptor affinities than with insulin receptor off-rates. The 2 rapid-acting insulin analogs aspart and lispro resembled human insulin on all parameters, except for a slightly elevated IGF-I receptor affinity of lispro. In contrast, the 2 long-acting insulin analogs, glargine and detemir, differed significantly from human insulin. The combination of the B31B32diArg and A21Gly substitutions provided insulin glargine with a 6- to 8-fold increased IGF-I receptor affinity and mitogenic potency compared with human insulin. The attachment of a fatty acid chain to LysB29 provided insulin detemir with reduced receptor affinities and metabolic and mitogenic potencies but did not change the balance between mitogenic and metabolic potencies. The safety implications of the increased growth-stimulating potential of insulin glargine are unclear. The reduced in vitro potency of insulin detemir might explain why this analog is not as effective on a molar basis as human insulin in humans.
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PMID:Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. 1086 53

Cyanate spontaneously transformed from urea increases as renal function decreased. Acting as a potential toxin, the active form of cyanate, isocyanic acid, carbamoylates amino acids, proteins, and other molecules, changing their structure, charge, and function. The resulting in vivo carbamoylation can modify the molecular activity of enzymes, cofactors, hormones, low-density lipoproteins, antibodies, receptors, and transport proteins. Antibodies specific for epsilon-amino-carbamoyl-lysine (homocitrulline) located carbamoylated proteins in situ in neutrophils, monocytes, and erythrocytes. Carbamoylated proteins were found in renal tissue from uremic patients but not in normal transplanted kidneys. The irreversible reaction with cyanate converts free amino acids (F-AAs) to carbamoyl-amino acids (C-AAs). The Carbamoylation Index (CI), C-AA/F-AA, quantifies the decrease of the F-AA pool for each essential amino acid. C-AAs contribute, in part, to malnutrition of uremia. C-AAs interfered with protein synthesis to lower 14C hemoglobin synthesis in human reticulocytes and osteocalcin synthesis in rat osteosarcoma-derived tissue culture. Insulin-sensitive glucose uptake was decreased 33% in cultured rat adipocytes by alpha-amino-carbamoyl-asparagine. alpha-Amino carbamoylation occurs primarily in F-AA, while epsilon-amino carbamoylation of lysine in protein occurs continuously during the protein life span. Protein catabolism releases epsilon-amino-carbamoyl-lysine. Quantitation of alpha versus epsilon carbamoylation may yield a more sensitive measurement of protein intake versus protein catabolism, and could be useful in decisions concerning the time to initiate dialysis or subsequent changes in dialysis prescription. Carbamoylated molecules can block, enhance, or be excluded from metabolic pathways, thereby influencing the fate of noncarbamoylated molecules. Although not an "all-or-none" phenomenon, urea-derived cyanate and its actions are contributing causes of toxicity in uremia.
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PMID:Carbamoylation of amino acids and proteins in uremia. 1116 93


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