Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transforming protein of simian sarcoma virus is homologous to the platelet-derived growth factor (PDGF) B-chain. Fibroblasts transformed with simian sarcoma virus constitutively produce a growth factor that stimulates the endogenous tyrosine kinase of PDGF receptors in an autocrine manner. Autophosphorylation of PDGF receptors upon ligand stimulation provides binding sites for Src homology 2 domains of intracellular signaling molecules, which thereby become activated. We have characterized the PDGF receptor-mediated signal transduction in NIH 3T3 cells transformed with a PDGF B-chain cDNA (Sis 3T3 cells) in the absence and presence of suramin, a polyanionic compound that quenches PDGF-induced mitogenicity and reverts the transformed phenotype of the Sis 3T3 cells. Our data show that in the presence of suramin the general level of tyrosine phosphorylation was decreased. Nevertheless, autophosphorylated receptors complexed with substrates persisted in the cells. Suramin had no effect on activation of phosphatidylinositol 3'-kinase or on tyrosine phosphorylation of phospholipase C-gamma and GTPase-activating protein of Ras. On the other hand, kinase activation of Src and Raf-1, phosphorylation of protein-tyrosine phosphatase 1D/Syp and Shc, and complex formation with Grb2 were greatly diminished by suramin. A possible explanation for our findings is that different PDGF receptor-coupled signaling pathways are active in different structural or functional compartments in the cell. Those pathways that are not affected by suramin might elicit distinct cellular responses, which are not sufficient for growth and transformation.
 ...
PMID:Compartmentalization of autocrine signal transduction pathways in Sis-transformed NIH 3T3 cells. 773 Mar 19

We previously reported that in transformed mouse sarcoma cells of spontaneous origin and in revertants transfected with a fos-cat fusion, the 600-bp c-fos promoter region provides chloramphenicol acetyltransferase activity. In the present study, we investigated the binding of transcriptional factor protein(s) to a region (-503 to -361) upstream of the sis (platelet-derived growth factor)-inducible factor (SIF)-binding element. Gel electrophoresis retardation (GER) assay clearly demonstrated the appearance of strong binding activity to a newly described fragment in the 142-bp region studied. Further analysis using synthetic oligodeoxyribonucleotides and GER defined a binding region of 30 bp (AvaI-AvaII) from -503 to -472 that partially overlaps with a region known to bind fos promoter binding site 2 (FBS2). DNase I footprint analysis discovered a novel sequence in the upstream region of the c-fos promoter to which protein(s) in nuclear extracts from various mouse and human cells bind. This factor(s) is not identical to most known transcriptional factors present in the promoter region of nuclear oncogenes. A proximal part of this fragment is very conservative and contains several AP-2-like-binding sites.
 ...
PMID:Characterization of a 142-bp fragment of the murine c-fos oncogene promoter upstream of the SIF-binding element. 819 66

Regulation of the platelet-derived growth factor (PDGF)-alpha receptor is thought to play an important role in pathophysiologic processes. Previously, we have reported that IL-1 has the potential to regulate PDGF-induced biologic activity in both normal human osteoblastic cells and the human osteoblastic cell line, MG-63, by decreasing the expression of PDGF-alpha receptor mRNA. In the present studies, we analyzed the effects of IL-1 on transcription rates and the stability of PDGF-alpha receptor mRNA in MG-63 cells. The data indicate that the t1/2 of PDGF-alpha receptor mRNA is approximately 3.3 h after incubation with the RNA II polymerase transcription inhibitor 5,6-dichloro-1 beta-D-ribofuranosylbenzimidazole (DRB). Approximately the same t1/2 (3.1 h) was obtained when osteoblastic cells were incubated with IL-1. The t1/2 for PDGF-alpha receptor mRNA for cells incubated with both IL-1 and DRB was 3 h. This finding suggests that the levels of PDGF-alpha receptor mRNA transcripts are not regulated by post-transcriptional mechanisms. Results of nuclear run-on analysis were consistent with this conclusion, demonstrating that IL-1 modulates PDGF-alpha receptor gene expression at the transcriptional level. Surprisingly, incubation of cells with cycloheximide also caused down-regulation of PDGF-alpha receptor mRNA, which suggests that synthesis of a labile factor is necessary for constitutive expression. The functional consequence of down-regulation of PDGF-alpha receptors by IL-1 was also assessed. By using chemotaxis assays, we demonstrated that IL-1 significantly inhibited PDGF-AA-mediated migration in human MG-63 osteoblastic sarcoma cells.
 ...
PMID:IL-1 down-regulates platelet-derived growth factor-alpha receptor gene expression at the transcriptional level in human osteoblastic cells. 820 49

PDGF heterodimer of A and B chains, a complete mitogen for 3T3 mouse fibroblasts, exemplifies those growth factors interacting with membrane associated tyrosine kinase receptors. Its binding to the PDGF-receptors results in receptor dimerization and subsequent activation of tyrosine kinase activity in the cytoplasmic protein domain, autophosphorylation of the receptor being the first event in the transduction cascade. Before the ligand-receptor complex is internalized and degraded, receptor stimulation is transmitted to the general transduction network, in which several tyrosine kinase substrates are activated by phosphorylation and changes the cytoplasmic biochemistry. These changes include cytoplasmic alkalinization, increases in the intracellular concentration of cyclic-AMP and Ca2+ and activation of protein kinase C through the degradation of phosphoinositides. The known substrates recruited by the PDGF-receptor association are phosphatidylinositol-3'-kinase, ras-GTPase-activating protein, phospholipase C-gamma, serine-threonine kinase Raf-1 and src and src-related tyrosine kinases. Upon binding of PDGF to its receptor, transactivation of transcriptional and nuclear factors such as c-fos and c-myc genes and dephosphorylation of c-jun occurs, V-sis, the oncogen of the simian sarcoma virus (SSV), is highly homologous to the c-sis/PDGF-B gene that encodes the homodimer of the B-chain of the PDGF receptor. Cells transformed by SSV have been studied as a model system for the autocrine stimulation of the PDGF receptor.
 ...
PMID:Platelet derived growth factor/tyrosine kinase receptor mediated proliferation. 822 Jan 10

Platelet-derived growth factor (PDGF) is a potent mitogen for a variety of cell types. PDGF is made up as dimers of A and B polypeptide chains which are combined to generate the three isoforms of PDGF (AA, AB, BB). These bind with different specificities and affinities to two types of cell surface receptors (the alpha-receptor and the beta-receptor), both being members of the protein tyrosine kinase family of growth factor receptors. A number of human tumor cell lines, particularly those established from glioma and sarcoma, have been shown to produce PDGF and express the cognate receptor type. In these instances, tumor cell growth may be enhanced by an autocrine receptor activation. In other tumor cell types, where PDGF is produced in the absence of receptor expression, the growth factor may act in a paracrine fashion. This view is supported by our recent finding that human melanoma cells that have been stably transfected with a PDGF B-chain cDNA, elicit a stroma response when transplanted to nude mice.
 ...
PMID:Platelet-derived growth factor. Structure, function and implications in normal and malignant cell growth. 832 51

Recent studies indicate that insulin-like growth factor-II (IGF-II) acts as an autocrine differentiation factor for skeletal myoblasts in culture. IGF-II mRNA and protein are induced as early events in muscle differentiation, and the rate and extent of IGF-II secretion correlate with both biochemical and morphological differentiation. Here we show that IGF-II also functions as an essential survival factor during the transition from proliferating to differentiating myoblasts. Stably transfected C2 muscle cell lines were established in which a mouse IGF-II cDNA was expressed in the antisense orientation relative to the constitutively active Moloney sarcoma virus promoter. IGF-II antisense cells proliferated normally in growth medium containing 20% serum but underwent rapid death when placed in low serum differentiation medium. Death was accompanied by characteristic markers of apoptosis with more than 90% of cells showing DNA fragmentation within 12-16 h. Myoblast death was prevented by IGF-I, des [1-3] IGF-I, IGF-II, and insulin with a dose potency consistent with activation of the IGF-I receptor; death also could be blocked by the protein synthesis inhibitor, cycloheximide. Exogenous IGFs additionally stimulated passage through a single cell cycle and subsequently induced terminal differentiation. Cell survival and cell cycle progression also were enhanced by fibroblast growth factor-2 and platelet-derived growth factor-bb, but these peptides did not promote differentiation. Our results define a novel system for studying apoptotic cell death and its prevention by growth factors, underscore the importance of IGF action in minimizing inappropriate cell death, and indicate that shared signal transduction pathways may mediate myoblast survival in vitro.
 ...
PMID:Insulin-like growth factor-II is an autocrine survival factor for differentiating myoblasts. 862 86

Chromosomal translocations resulting in chimaeric transcription factors underlie specific malignancies, but few authentic target genes regulated by these fusion proteins have been identified. Desmoplastic small round-cell tumour (DSRT) is a multiphenotypic primitive tumour characterized by massive reactive fibrosis surrounding nests of tumour cells. The t(11;22)(p13;q12) chromosomal translocation that defines DSRT produces a chimaeric protein containing the potential transactivation domain of the Ewing-sarcoma protein (EWS) fused to zinc fingers 2-4 of the Wilms tumour suppressor and transcriptional repressor WT1 (refs 2,3). By analogy with other EWS fusion products, the EWS-WT1 chimaera may encode a transcriptional activator whose target genes overlap with those repressed by WT1 (ref. 4). To characterize its functional properties, we generated osteosarcoma cell lines with tightly regulated inducible expression of EWS-WT1. Expression of EWS-WT1 induced the expression of endogenous platelet-derived growth factor-A (PDGFA), a potent secreted mitogen and chemoattractant whose promoter contains the many potential WT1-binding sites. Native PDGFA was not regulated by wild-type WT1, indicating a difference in target gene specificity between this tumour suppressor and its oncogenic derivative. PDGFA was expressed within tumour cells in primary DSRT specimens, but it was absent in Wilms tumours expressing WT1 and Ewing sarcomas with an EWS-Fli translocation. We conclude that the oncogenic fusion of EWS to WT1 in DSRT results in the induction of PDGFA, a potent fibroblast growth factor that contributes to the characteristic reactive fibrosis associated with this unique tumour.
 ...
PMID:The EWS-WT1 translocation product induces PDGFA in desmoplastic small round-cell tumour. 935 95

Platelet-derived growth factor (PDGF) has a targeted activity on mesenchymal cells, but the in vivo effects of PDGF are not well understood. We have applied about 3 microg of PDGF-A and PDGF-B on the differentiated chorioallantoic membrane (CAM) of 13-day-old chick embryos. After 1-3 days, specimens were evaluated macroscopically, histologically with semi- and ultrathin sections, and immunohistologically with antibodies against smooth muscle alpha-actin (alphaSMA), desmin, and fibronectin (FN). Proliferation studies were performed according to the 5-bromo-2-deoxyuridine (BrdU)/anti-BrdU method. We did not observe effects of PDGF-A. PDGF-B induced proliferation of fibrocytes and their transformation into myofibroblasts. Bundles of spindle-shaped myofibroblasts accumulated beneath the chorionic epithelium. These cells were strongly positive for alphaSMA and FN, but negative for desmin. They possessed a well developed rough endoplasmic reticulum and bundles of microfilaments anchoring in the cell membrane. Our results suggest that PDGF-B is a "transforming" growth factor with important functions during formation of granulation tissue which are closely comparable to the effects of the PDGF-B-like protein of simian sarcoma virus. PDGF-B also induced vascular alterations in the CAM, which, however, appeared to be a secondary effect. While the intra-chorionic capillaries were lost, an accumulation of small vessels positive for alphaSMA was observed. This indicates a function for PDGF-B during segregation of main vessels from a primary vascular plexus.
 ...
PMID:Platelet-derived growth factor-B induces transformation of fibrocytes into spindle-shaped myofibroblasts in vivo. 956 84

Little is known about the regulation of sarcoma proliferation by hormones and/or growth factors. We therefore characterised the in vitro proliferative influence on eight sarcoma cell lines of the platelet-derived growth factor, the insulin-like growth factor 1, triiodothyronine, the epidermal growth factor, the luteinising-hormone-releasing hormone, progesterone, gastrin and 17 beta-oestradiol. The influence of the different factors on the proliferation of sarcoma cell lines was measured by the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Two culture media were studied: (1) a nutritionally poor medium containing 2% of fetal calf serum and (2) a nutritionally rich one containing 5% or 10% FCS both with and without the addition of non-essential amino acids. The results were analysed either by conventional statistical analyses or by a classification method based on a decision-tree approach developed in Machine Learning. This latter method was also compared to other classifiers (such as logistic regression and k nearest neighbours) with respect to its accuracy of classification. Monovariate statistical analysis showed that each of the eight cell lines exhibited sensitivity to at least one factor, and each factor significantly modified the proliferation of five or six of the eight cell lines under study. Of these eight lines one of fibrosarcoma origin was the most "factor-sensitive". Decision-tree-related data analysis enabled the specific pattern of factor sensitivity to be characterised for the three histological types of cell line under study. The effects of hormone and growth factors are significantly influenced by the type of culture medium used. The method used appeared to be an accurate classifier for the kind of data analysed. Sarcoma proliferation can be modulated, at least in vitro, by various hormones and growth factors, and the proliferation of each histopathological type exhibited a distinct sensitivity to different hormone and/or growth-factors.
 ...
PMID:The in vitro influence of eight hormones and growth factors on the proliferation of eight sarcoma cell lines. 961 41

Uteroglobin (UG) is a steroid-inducible, multifunctional, secreted protein with antiinflammatory and antichemotactic properties. Recently, we have reported a high affinity UG-binding protein (putative receptor), on several cell types, with an apparent molecular mass of 190 kDa (Kundu, G. C., Mantile, G., Miele, L., Cordella-Miele, E., and Mukherjee, A. B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 2915-2919). Since UG is a homodimer in which the 70 amino acid subunits are connected by two disulfide bonds, we sought to determine whether UG monomers also interact with the 190-kDa UG-binding protein and if so, whether it has the same biological activity as the dimer. Surprisingly, we discovered that in addition to the 190-kDa species, another protein, with an apparent molecular mass of 49 kDa, binds reduced UG with high affinity and specificity. Both 49- and 190-kDa proteins are readily detectable on nontransformed NIH 3T3 and some murine cancer cells (e. g. mastocytoma, sarcoma, and lymphoma), while lacking on others (e.g. fibrosarcoma). Most interestingly, pretreatment of the cells, which express the binding proteins, with reduced UG dramatically suppresses extracellular matrix (ECM) invasion, when such treatment had no effect on fibrosarcoma cells that lack the UG-binding proteins. Tissue-specific expression studies confirmed that while both 190- and 49-kDa UG-binding proteins are present in bovine heart, spleen, and the liver, only the 190-kDa protein is detectable in the trachea and in the lung. Neither the 190-kDa nor the 49-kDa protein was detectable in the aorta. Purification of these binding proteins from bovine spleen by UG-affinity chromatography and analysis by SDS-polyacrylamide gel electrophoresis followed by silver staining identified two protein bands with apparent molecular masses of 40 and 180 kDa, respectively. Treatment of the NIH 3T3 cells with specific cytokines (i.e. interleukin-6) and other agonists (i.e. lipopolysaccharide) caused a substantially increased level of 125I-UG binding but the same cells, when treated with platelet-derived growth factor, tumor necrosis factor-alpha, interferon-gamma, and phorbol 12-myristate 13-acetate, did not alter the UG binding. Taken together, these findings raise the possibility that UG, through its binding proteins, plays critical roles in the regulation of cellular motility and ECM invasion.
 ...
PMID:Uteroglobin (UG) suppresses extracellular matrix invasion by normal and cancer cells that express the high affinity UG-binding proteins. 971 16


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>