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131.
Genetic alteration of endothelial heparan sulfate selectively inhibits tumor angiogenesis 总被引:1,自引:0,他引:1 下载免费PDF全文
Fuster MM Wang L Castagnola J Sikora L Reddi K Lee PH Radek KA Schuksz M Bishop JR Gallo RL Sriramarao P Esko JD 《The Journal of cell biology》2007,177(3):539-549
To examine the role of endothelial heparan sulfate during angiogenesis, we generated mice bearing an endothelial-targeted deletion in the biosynthetic enzyme N-acetylglucosamine N-deacetylase/N-sulfotransferase 1 (Ndst1). Physiological angiogenesis during cutaneous wound repair was unaffected, as was growth and reproductive capacity of the mice. In contrast, pathological angiogenesis in experimental tumors was altered, resulting in smaller tumors and reduced microvascular density and branching. To simulate the angiogenic environment of the tumor, endothelial cells were isolated and propagated in vitro with proangiogenic growth factors. Binding of FGF-2 and VEGF(164) to cells and to purified heparan sulfate was dramatically reduced. Mutant endothelial cells also exhibited altered sprouting responses to FGF-2 and VEGF(164), reduced Erk phosphorylation, and an increase in apoptosis in branching assays. Corresponding changes in growth factor binding to tumor endothelium and apoptosis were also observed in vivo. These findings demonstrate a cell-autonomous effect of heparan sulfate on endothelial cell growth in the context of tumor angiogenesis. 相似文献
132.
The current limited understanding of the free energy contributions of metal-protein interactions toward metalloprotein stability is largely due to an inability to separate the energetics of the metal-ligand and protein-protein interactions. In order to elucidate the thermodynamic contribution of a Zn(II)-(S.Cys)4 site toward metalloprotein stability relevant to classic structural Zn(II) sites, the reaction of {Zn(II)(H2O)6}2+ with a minimal, unstructured, tetracysteine 16-mer peptide, GGG, is described. Isothermal titration fluorimetry over the pH range of 4.5 to 9.0 is used to measure the free energy of Zn(II) binding to the model peptide GGG. The data show that, in the absence of proton competition, Zn(II) binds to the Cys4 coordination sphere with a Kd of 60 aM, indicating that the Zn(II)-(S.Cys)4 interaction can provide up to 22.1 kcal mol-1 in driving force for protein stabilization, folding, and/or assembly. Isothermal titration calorimetry shows that Zn(II)-GGG formation is entropy driven because of water release from both the metal and the peptide scaffold. At pH 7.0, where the Zn(II)-GGG Kd value is 8.0 pM, the reaction releases 3.8 protons, is endothermic with DeltaHrxn of +6.4 kcal mol-1, and entropy driven with DeltaSrxn of +72 cal K-1 mol-1. At pH 8.0, where the peptide is partially deprotonated prior to Zn(II) binding, the 1.0 fM Zn(II)-GGG Kd value reflects a Zn(II) complexation reaction involving the release of 2.5 protons, which is slightly exothermic, with DeltaHrxn of -2.0 kcal mol-1, and largely entropy driven, with DeltaSrxn of +61 cal K-1 mol-1. At pH 5.5, where proton competition weakens the Kd to 4.0 microM, only 3.2 protons are released upon Zn(II) binding, the reaction is endothermic, with DeltaHrxn of +7.7 kcal mol-1, and entropy driven, with DeltaSrxn of +51 cal K-1 mol-1. Likely an intrinsic property of Zn(II)-(S.Cys)4 sites, the entropy driven binding of Zn(II) reflects the proton dependent chemical speciation of the Zn(II)-(S.Cys)4 peptide complex and its effects on modulating the dehydration of both the peptide and metal. Furthermore, the Zn(II) binding thermodynamics of a variety of Zn(II) proteins at pH 7.0 reveals the presence of enthalpy-entropy compensation (EEC) phenomena in nature. 相似文献
133.
Spectroscopic studies on Zn(II)-phthalocyanine in homogeneous and microheterogeneous systems 总被引:1,自引:0,他引:1
The absorption and fluorescence properties of Zn2+-phthalocyanine (Zn-Pc) have been characterized in homogeneous and microheterogeneous media. By our preparation procedure, the phthalocyanine can be associated in a monomeric state with cationic micelles, unilamellar liposomes, and low-density lipoproteins; the distribution of Zn-Pc in the hydrophobic phases appears to be controlled by the nature of the lipid environment. The potential use of liposome-bound Zn-Pc for photosensitization studies in aqueous media and for phototherapeutic applications in vivo is briefly discussed. 相似文献
134.
Biosynthesis and fate of proteoglycans in cartilage and bone during development and mineralization 总被引:2,自引:0,他引:2
M Y Tian M Yanagishita V C Hascall A H Reddi 《Archives of biochemistry and biophysics》1986,247(1):221-232
Subcutaneous implantation of demineralized bone matrix in rats induces migration of host cells into the site and results in the sequential development of cartilage and bone. The biosynthesis and metabolic fate of proteoglycans in the plaques at the bone matrix implantation site were investigated by [35S]sulfate labeling in vivo. 35S-Labeled proteoglycans were extracted with 4 M guanidine HCl and purified by DEAE-Sephacel chromatography. Analysis of proteoglycans on Sepharose CL-2B chromatography showed two major peaks at Kd = 0.28 and 0.68 (peaks I and II, respectively). Peak I proteoglycan has a high buoyant density and contains chondroitin sulfate chains of average Mr = 20,000. Peak II proteoglycan has a lower average buoyant density and contains dermatan sulfate chains of average Mr = 33,000. Throughout the endochondral bone development sequence, peak II proteoglycan predominates. Peak I was low on Day 3, became prominent on Day 7 (approximately 30% of the total radioactivity), and declined after Day 9. The calculated half-lives of peak I and II proteoglycans labeled on Day 7 were about 1.8 and 2.8 days, respectively. After the initiation of osteogenesis, a species of mineral-associated proteoglycan was extracted with a 4 M guanidine HCl solvent containing 0.5 M EDTA. This proteoglycan has a small hydrodynamic size (Kd = 0.38 on Sepharose CL-6B chromatography) and shows a long half-life, about 6 days. 相似文献
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Significant amounts of arginase activity were found in homogenates of submaxillary salivary gland and epididymis, as well as of liver, kidney, mammary gland, and small intestine. The isoelectric point of arginase solubilized from kidney was at pH 7.0 in contrast to that of pH 9.4 characteristic of hepatic arginase in rat. The isozymic variants of arginase in the different tissues were identified by their electrophoretic migration on polyacrylamide gels and by titration of the enzymes against antibody prepared against purified rat liver arginase. Antibody titrations confirmed the indications obtained by electrophoresis that one type of arginase is limited to hepatic tissues (and possibly submaxillary gland) while the other type is found in all other tissues. The physiological role of arginase in hepatic tissues has been previously associated with the urea cycle; the possible function of arginase in proline synthesis in other tissues remains to substantiated. 相似文献