摘要:

AbstractThe IGFBPs bind to and modulate the function of the IGFs in various ways. Human IGFBP-4 inhibits IGF mediated cell proliferation. The IGFBP exon-encoded regions were aligned and secondary structure predictions for hIGFBP-4 were developed yielding predicted 3D co-ordinates for each such region of hIGFBP-4. The exon 1 encoded region is the most conserved among the IGFBPs. That of hIGFBP-4 is predicted as an array ofβ-strands that include the glycine and cysteine rich IGFBP concensus pattern and that terminate with a helix. The exon 2 encoded region is the most variable among the IGFBPs. That of hIGFBP-4 is predicted as mostly an amphipathic helix. The remaining regions are also conserved among the IGFBPs. Those of hIGFBP-4 are also predicted to contain helices. The predicted structure of hIGFBP-4 comprises amino terminalβ-strands with four helices in the carboxy terminal two thirds of the molecule.

ISSN:0897-7194    

DOI:10.3109/08977199509028963

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

AbstractMouse granulocyte-macrophage colony-stimulating factor (mGM-CSF) proteins with substitutions for residues located withinα-helix D were examined for biological activity and receptor binding properties. Alanine substitutions of the surface exposed positions indicated that several residues contribute to the ligand-receptor interface. Position K108and particularly D102appeared to dominate the binding epitope recognized by mGM-Rα. Several amino acid substitutions were made for K108which reduced binding with concommitant losses in bioactivity. Substitutions for D102resulted in binding affinities less than 0.1% that of the wild-type mGM-CSF and bioactivity decreased to 1.0%. Comparative analysis using high and low affinity binding conditions indicated that mGM-Rβbinding was unaffected by these mutations.

ISSN:0897-7194    

DOI:10.3109/08977199509028964

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

AbstractRecent studies have suggested that the membrane proximal region of the cytoplasmic domain of the erythropoietin receptor and other members of the cytokine receptor superfamily may be required for signal transduction. Expression of several deletion mutants of the erythropoietin receptor in Ba/F3 cells showed that a region with homology to the interleukin-2 receptorβ-chain which includes Box 2 is not essential for erythropoietin-dependent cell proliferation. However, a region between Box 1 and Box 2 contains essential residues for proliferative response. Expression of mutant receptors was confirmed by reverse transcriptase-PCR analysis and by Western blotting, which also showed no evidence for expression of endogenous wild-type receptor. These findings are in direct conflict with previously reported mutagenesis studies of the erythropoietin receptor suggesting that mitogenesis may be channelled through more than one pathway depending on the complement of signaling molecules expressed in the cell.

ISSN:0897-7194    

DOI:10.3109/08977199509028965

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

AbstractWe have recently found that the inhibitor of plasmacytoma cell growth, restrictin-P, is a stroma derived activin A and that it is an antagonist of interleukin-6 and interleukin-11. The present study was aimed at determining the mode by which this cytokine kills its target cells. On addition of the cytokine there was little or no net increase in cell number, depending on the specific target cells. All plasmacytoma cell lines tested exhibited a similar time dependent inhibition of DNA synthesis and a G0/G1shift in the cell cycle. Electron microscope examination revealed classical apoptotic features i.e. chromatin condensation and membrane blebbing. DNA fragmentation, measured qualitatively and quantitatively, occurred in all cytokine treated plasmacytoma cell lines. Bovine activin A had an identical capacity to reduce cell viability, to induce G0/G1shift and to cause DNA fragmentation. X-ray microanalysis of intracellular ions revealed an increase in calcium ions, following exposure of plasmacytoma cells to restrictin-P, accompanied by a decrease in phosphor ions. The cytotoxicity of the inhibitor was augmented in an additive manner by cycloheximide (CHX) indicating that the process did not require de novo protein synthesis. This study thus shows that restrictin-P/stromal activin A kills its target cells by inducing apoptosis. This effect was mediated by subnanogram concentrations and therefore may represent one physiological function of this pleiotropic cytokine.

ISSN:0897-7194    

DOI:10.3109/08977199509028966

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

AbstractSolid tumor growth is dependent upon angiogenesis, a process by which soluble factors released from a tumor induce the sprouting and growth of new blood vessels from nearby venules into the tumor. This process of tumor vascularization provides tumor cells with nutrients, oxygen, and an enhanced ability to establish metastasis at peripheral sites by migration through the circulatory system. Vascular endothelial growth factor is a potent angiogenic factor that is expressed at low levels by most normal cells, can be upregulated in normal cells by exposure to hypoxia or phorbol esters, and exhibits high levels of constitutive expression in some human tumors and tumor cell lines. The mechanism underlying the stable change that results in VEGF overexpression in tumors is unknown. Here, we demonstrate that both hypoxia and TPA induce stabilization of VEGF mRNA, that stabilization by hypoxia is rapidly reversible upon reexposure to normoxia, and that tumor cell lines exhibiting constitutive overexpression of VEGF also exhibit constitutive stabilization of VEGF transcripts. Stabilized VEGF transcripts in tumor cells are refractile or nearly refractile toward further stabilization by TPA or hypoxia, respectively. Furthermore, cycloheximide induces stabilization of VEGF mRNA in normal cells but has no effect on VEGF transcript stability in tumor cells that contain stabilized transcripts. These results suggest that normal signal transduction mechanisms mediate stabilization of the VEGF mRNA, and that mutations in this regulatory pathway in tumor cells may lead to chronic message stabilization, overexpression of VEGF proteins, and ensuing tumor vascularization.

ISSN:0897-7194    

DOI:10.3109/08977199509028967

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor

摘要:

AbstractNIH-3T3 cells transformed with met/HGF receptor gene proliferate in the absence of serum and growth factors. Immunocytochemical staining with anti-HGF antibody revealed intense HGF staining in the transfected cells. Additionally, these cells secrete bioactive HGF as evidenced by the ability of the conditioned media to stimulate met/HGF receptor phosphorylation in epithelial cells, and to promote migration of bovine adrenal capillary endothelial cells in a modified Boyden chamber assay. The migration of endothelial cells could be specifically inhibited by anti-HGF antibody but not by an irrelevant antibody. Suramin, a drug known to disrupt ligand-receptor interactions, inhibits the serum and growth-factor free proliferation, and the endogenous phosphorylation of met/HGF receptor in the transformed cells. Taken together, our data suggests an autocrine mode of transformation in NIH-3T3 cells transfected with met/HGF receptor gene.

ISSN:0897-7194    

DOI:10.3109/08977199509028968

出版商:Taylor&Francis    

年代:1995

数据来源: Taylor