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

Two murine cell lines that overexpress v-sis/PDGF-2 were used to study the mechanism of cell transformation by SSV (simian sarcoma virus). In contrast to the parental cells that are phenotypically normal and serum-dependent for growth, v-sis-overexpressing cells grow in PDGF-free plasma medium, are unable to enter the G0 state and are highly tumorigenic. Analysis of the expression of some growth factor-induced early response genes in v-sis-overexpressing cells revealed: (a) high and constitutive c-myc mRNA levels in SSV-NRK cells; (b) unaltered levels of fra-1, fos B, jun B and krox 20 transcripts; (c) high and constitutive FOS staining due to c-FOS and FOS-related protein(s); (d) constitutive c-JUN and higher JUN D expression. These results are compatible with a model in which endogenous production of v-sis/PDGF-2 leads to deregulated expression of key cellular transregulators that, in turn, alter the cells' transcriptional program leading to the transformed state and malignancy.
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PMID:Imbalanced expression of cellular nuclear oncogenes caused by v-sis/PDGF-2. 192 19

The v-sis transforming gene encodes the woolly monkey homologue of human platelet-derived growth factor (PDGF) polypeptide 2. After its synthesis on membrane bound polyribosomes, the glycosylated precursor dimerizes in the endoplasmic reticulum and travels through the Golgi apparatus. At the cell periphery, the precursor is processed to yield a dimer structurally analogous to biologically active PDGF. Small amounts of two incompletely processed forms are detectable in tissue culture fluids of simian sarcoma virus (SSV) transformants. However, the vast majority remains cell associated. Thus, this growth factor-related transforming gene product is not a classical secretory protein. These findings define possible cellular locations where the transforming activity of the sis-PDGF-2 protein may be exerted.
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PMID:The v-sis/PDGF-2 transforming gene product localizes to cell membranes but is not a secretory protein. 299 41

Platelet-derived growth factor (PDGF), a potent mitogen for mesenchymal cells, consists of PDGF-1 and PDGF-2 polypeptide chains which are linked by disulfide bonds. Sequence analysis has revealed that: (a) the PDGF-2 chain is encoded by the c-sis protooncogene, the cellular counterpart of the simian sarcoma viral oncogene; (b) the PDGF-1 and PDGF-2 chains are related; and (c) the PDGF-1 gene has no known viral homologue. We have previously shown that the PDGF-2 gene is expressed during 12-O-tetradecanoylphorbol-13-acetate (TPA) induced monocytic differentiation of human HL-60 leukemia cells. In the present study, PDGF-1 and PDGF-2 gene expression was compared in HL-60 cells, human THP-1 monocytic leukemia cells, and human monocytes. Uninduced HL-60 cells, uninduced THP-1 cells, and resting monocytes had no detectable PDGF-1 or PDGF-2 mRNA. In contrast, both PDGF-1 and PDGF-2 transcripts were detected in HL-60 cells and monocytes induced with TPA, while only PDGF-1 mRNA was found in TPA-treated THP-1 cells. Moreover, neither of these transcripts were found during drug induced granulocytic differentiation of HL-60 cells. Cycloheximide, an inhibitor of protein synthesis: (a) failed to increase PDGF-1 and PDGF-2 mRNA levels in uninduced HL-60 cells; (b) increased PDGF-2, but not PDGF-1, mRNA in resting monocytes; and (c) increased levels of PDGF-1 and PDGF-2 mRNA in HL-60 cells and monocytes treated with TPA. This effect of cycloheximide was related in part to stabilization of both transcripts. Thus, PDGF-1 and PDGF-2 genes are differentially regulated in myeloid cells, although they share common control mechanisms at the post-transcriptional level. Differential regulation of PDGF gene expression would result in altered chain composition of the PDGF protein and possibly changes in biological activity.
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PMID:Expression of the platelet-derived growth factor 1 and 2 genes in human myeloid cell lines and monocytes. 316 51

The autocrine effects of platelet-derived growth factor (PDGF) A- and B-chain homodimers (PDGF-AA and PDGF-BB) on rat-1 cells and human fibroblasts have been investigated by using human PDGF A- and B-chain cDNA clones expressed in a retroviral vector. Infection with replication-defective virus carrying the B-chain cDNA resulted in a phenotypical transformation resembling that induced by simian sarcoma virus. The resulting cells were focus forming in monolayer cultures, grew to high saturation densities, and formed large colonies in soft agar. The PDGF A-chain transfectants showed no transformed morphology and lacked focus-forming activity but grew to high saturation density in monolayer culture and formed small colonies in soft agar. A similar but weaker effect was obtained with an A-chain cDNA variant containing a 69-base-pair insertion in the 3' end of the protein-coding domain. A- and B-chain transfectants released PDGF receptor-competing activity into the medium, but only the medium conditioned by the B-chain transfectants possessed potent mitogenic activity on human fibroblasts. Both types of transfectants had downregulated levels of PDGF receptors; however, the B-chain transfectants were downregulated to significantly lower levels. Metabolic labeling and immunoprecipitations with PDGF antiserum showed that the PDGF B-chain protein was processed to a 24-kilodalton cell-associated and a 30-kilodalton secreted dimeric protein. The A-chain protein was rapidly secreted as a 31-kilodalton dimeric protein. The present study shows a marked difference in the autocrine effects of PDGF-AA and -BB expressed under the control of a retroviral promoter and suggests that different biological properties may be assigned to these two PDGF isoforms.
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PMID:Expression of recombinant platelet-derived growth factor A- and B-chain homodimers in rat-1 cells and human fibroblasts reveals differences in protein processing and autocrine effects. 340 17

Platelet-derived growth factor (PDGF), as purified from fresh human platelets, is a protein of relative molecular mass (Mr) 30,000 composed of two disulphide-linked subunit chains of similar size, named A and B (ref. 1). The dimer structure of PDGRF seems to be important for its biological effects, as reduction irreversibly inactivates the factor; it is not known, however, whether PDGF exists as a heterodimer or as a mixture of homodimers. Amino-acid sequence analysis has revealed that the A- and B-chains of human PDGF are related to each other, and that the B-chain is almost identical to part of the v-sis gene product of simian sarcoma virus (SSV). There is experimental evidence that a PDGF-like protein is indeed operational in SSV-induced transformation and the biologically active v-sis product is probably structurally similar to a putative dimer of PDGF B-chains. PDGF-like growth factors and/or a 4.2-kilobase (kb) c-sis transcript are present in several transformed mammalian cell lines and in certain nontransformed cells; cloned c-sis complementary DNA from human T cells transformed with human T-lymphotropic virus (HTLV) or from human endothelial cells contains the coding sequence for a putative PDGF B-chain precursor, but apparently lacks PDGF A-chain sequences. We have previously partially purified and characterized a PDGF-like growth factor from U-2 OS cells (osteosarcoma-derived growth factor, ODGF) and shown that this factor has structural, functional and immunological characteristics in common with PDGF. We describe here a procedure for the preparation of homogeneous ODGF, and provide evidence that this factor, which binds to the PDGF receptor, has a structure similar to a homodimer of PDGF A-chains.
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PMID:A human osteosarcoma cell line secretes a growth factor structurally related to a homodimer of PDGF A-chains. 345 80

Vascular endothelial cells have a central role in various pathophysiological responses such as acute inflammation, wound healing and atherogenesis. The anatomical position of endothelial cells between blood leukocytes and the surrounding vascular smooth muscle cells or stromal fibroblasts may intensify and focus the effects of released endothelial cell products. Endothelial cells in culture produce a platelet-derived growth factor (PDGF)-like mitogen. PDGF purified from platelets is a basic protein with an apparent relative molecular mass (Mr) of approximately 30,000 (reviewed in refs 2, 3) and is believed to comprise two polypeptide chains, PDGF-A and PDGF-B (also referred to as PDGF-1 and PDGF-2; refs 5, 6). Sequence analysis of PDGF B chain has revealed a striking homology with the predicted sequence of p28sis, the transforming protein of simian sarcoma virus. sis-Homologous transcripts have been detected by Northern blot analysis of RNA from cultured endothelial cells. However, there are no structural data available on either the protein product or the messenger RNA to establish the identity of the endothelial-derived mitogen with either chain of PDGF. Here we report the isolation and complete sequence analysis of a sis-homologous complementary DNA clone from human endothelial cells, providing an opportunity to study the structure of sis as transcribed by a normal (untransformed) cell. Our results establish that normal human endothelial cells in culture express the B chain of PDGF, and that endothelial-derived PDGF B chain is synthesized as a predicted precursor polypeptide of Mr 27,281.
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PMID:Cultured human endothelial cells express platelet-derived growth factor B chain: cDNA cloning and structural analysis. 403 72

Antisera to synthetic peptides representing sequences of both chains of platelet-derived growth factor (PDGF) were used to structurally analyze PDGF isolated from outdated human platelets and PDGF-like proteins in normal and transformed cells. Most PDGF isolated from platelets did not contain the carboxyl portion of PDGF-2 in contrast to p20sis, the major form of p28sis detected in simian sarcoma virus-transformed cells. In addition, higher molecular weight forms of molecules containing PDGF-1 and PDGF-2 sequences were detected in all cell lines tested. These lines were heterogeneous with respect to species, cell type, and transforming agent.
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PMID:Detection of high molecular weight forms of platelet-derived growth factor by sequence-specific antisera. 649 5

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.
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PMID:Compartmentalization of autocrine signal transduction pathways in Sis-transformed NIH 3T3 cells. 773 Mar 19

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.
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PMID:Platelet-derived growth factor. Structure, function and implications in normal and malignant cell growth. 832 51