Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P39060 (endostatin)
 2,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endostatin, a M(r) 20,000 fragment of collagen XVIII, is able to inhibit angiogenesis and induce apoptosis in endothelial cells in vivo. We analyzed the effectsof recombinant endostatin on human microvascular endothelial cells, focusing on pericellular plasminogen activation and its targeting by the focal adhesion-associated cytoskeletal structures. Analysis of the proteolytic plasminogen activator system revealed that endostatin modulates the distribution of soluble and cell surface-associated urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor, type 1 (PAI-1). Casein zymographic and immunoprecipitation analyses indicated that endostatin exerts its effects by decreasing the levels of soluble uPA and PAI-1 and their complexes in a dose-dependent manner. Immunofluorescence analysis of cell surface-associated uPA indicated that endostatin treatment caused the redistribution of receptor-bound uPA from focal contacts, resulting in diffuse cell surface staining. In accordance with this observation, immunofluorescence staining of the urokinase receptor revealed that endostatin treatment removed uPAR from focal adhesions. Accordingly, endostatin caused a rapid disassembly of focal adhesions as observed by immunofluorescence analysis of the focal adhesion proteins vinculin and paxillin. A prominent change in the cytoskeletal architecture was observed as the actin stress fiber network was dissociated in response to endostatin treatment. The effect of focal adhesion disassembly was reversible, persisting from 1 h up to 6 h. Our results suggest that the antiangiogenic activity of endostatin involves the modulation of focal adhesions and actin stress fibers and the down-regulation of the urokinase plasminogen activator system.
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PMID:Endostatin-induced modulation of plasminogen activation with concomitant loss of focal adhesions and actin stress fibers in cultured human endothelial cells. 1152 48

Fibrinolysis is a precisely orchestrated process in which fibrin-containing thrombi are solubilized. Several receptors regulate this process by localizing proteolytic activity to the cell surface. One such receptor is annexin II, a calcium and phospholipid-binding protein. Annexin II serves as a profibrinolytic coreceptor for both plasminogen and tissue plasminogen activator on the surface of endothelial cells and facilitates the generation of plasmin. The dysregulation of fibrinolytic assembly on endothelial cells may lead to atherothrombotic disease. In addition to its role in fibrinolysis at the surface of endothelial cells, annexin II may play other potential cellular roles. For example, the overexpression of annexin II on the surface of leukemic cells and cell lines derived from acute promyelocytic leukemia correlates with both the clinical manifestation of bleeding and the in vitro ability of the leukemic cells to generate plasmin. The abundant presence of annexin II on the surface of other cell types including monocytic cell lines and different cancer cells may contribute to their invasive potential through extracellular matrix either by generation of plasmin or, by plasmin-mediated proteolytic activation of other metalloproteinases. This dissolution of extracellular matrix may also cause the release of potent matrix-bound angiogenic factors such as VEGF and FGF. On the other hand, by increasing the pool of plasmin, a precursor to an important anti-angiogenic factor, angiostatin, and by fragmentation of collagen XVIII (a precursor to the anti-angigenic factor, endostatin) by plasmin-activated metalloproteases, annexin II could play a pivotal physiological role in the pro- and anti-angiogenic switch mechanism.
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PMID:Annexin II: a plasminogen-plasminogen activator co-receptor. 1181 88

Restin, a homologous protein of endostatin (62% homology), is the NC domain of collagen XV at C-terminal. The recombinant restin expressed in E. coli had the ability to suppress the proliferation of bovin aortic endothelial cells and cause apoptosis. In this report, mouse restin gene was fused with a sequence of human plasminogen signal peptide by PCR and cloned into eukaryotic expression vector pCDNA3. The plasmid containing restin gene was named pCDNAXV and was transfected into human hepatoma cell line Bel7404. Stable transfected clones were screened and expression of restin was confirmed by RT-PCR and Western blot. The proliferated cells were injected subcutaneusly into nude mice. The growth of tumors formed by cells transfected with restin gene was much slower than that of control group. These results indicated that the expressed restin in vivo could suppress the growth of tumor, and this suppression might be achieved by restraining angiogenesis since the restin had no effect on the proliferation of tumor cells. At the same time, this report provided a new method to investigate the effect of anti-angiogenetic proteins on the tumor growth.
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PMID:[Restin expressed in vivo suppresses the growth of tumors in nude mice]. 1219 58

Tissue-type plasminogen activator (tPA) regulates fibrin clot lysis by stimulating the conversion of plasminogen into the active protease plasmin. Fibrin is required for efficient tPA-mediated plasmin generation and thereby stimulates its own proteolysis. Several fibrin regions can bind to tPA, but the structural basis for this interaction is unknown. Amyloid beta (Abeta) is a peptide aggregate that is associated with neurotoxicity in brains afflicted with Alzheimer's disease. Like fibrin, it stimulates tPA-mediated plasmin formation. Intermolecular stacking of peptide backbones in beta sheet conformation underlies cross-beta structure in amyloid peptides. We show here that fibrin-derived peptides adopt cross-beta structure and form amyloid fibers. This correlates with tPA binding and stimulation of tPA-mediated plasminogen activation. Prototype amyloid peptides, including Abeta and islet amyloid polypeptide (IAPP) (associated with pancreatic beta cell toxicity in type II diabetes), have no sequence similarity to the fibrin peptides but also bind to tPA and can substitute for fibrin in plasminogen activation by tPA. Moreover, the induction of cross-beta structure in an otherwise globular protein (endostatin) endows it with tPA-activating potential. Our results classify tPA as a multiligand receptor and show that cross-beta structure is the common denominator in tPA binding ligands.
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PMID:Tissue-type plasminogen activator is a multiligand cross-beta structure receptor. 1241 83

Endostatin, a C-terminal subfragment of collagen XVIII, and angiostatin, a family of fragments originating from the NH(2)-terminal portion of plasminogen, have been described as potent inhibitors of angiogenesis and malignant growth. We have earlier reported the presence of angiostatin fragments in urine from cancer patients. In this study, we investigated the occurrence of endostatin and the correlation between the amounts of endostatin and angiostatin in urine collected from 104 patients with different types of malignancies and in 16 controls. The amounts of endostatin were measured with a commercial immunoassay. Angiostatin fragments were quantitated by Western blot analysis. Only small amounts of endostatin were observed, both in patients and controls, and there was no significant difference in the amount of endostatin between the patients and the controls. Both endostatin and angiostatin concentrations in the urine showed a strong dependence on impaired kidney function, especially tubulus function, measured as the amount of urine alpha(1)-microglobulin. Interestingly, there was no significant correlation between endostatin and angiostatin concentrations in the patients with impaired kidney function (elevated urine albumin or urine alpha(1)-microglobulin), suggesting a possible difference in circulating concentrations of these inhibitors.
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PMID:Low levels of endostatin in the urine from patients with malignant disease. 1249 78

Plasminogen-related protein B (PRP-B) closely resembles the N-terminal plasminogen activation peptide, which is released from plasminogen during conversion to plasmin. We have previously demonstrated that the steady-state level of mRNA encoding PRP-B is increased within tumor tissues, and that recombinant PRP-B antagonizes neoplastic growth when administered systemically to mice harboring tumors, but no insights into the cell targets of PRP-B have been presented. Employing serum-free medium optimized for culturing human endothelial or smooth muscle cells, we show that recombinant PRP-B inhibits basic fibroblast growth factor-dependent cell migration for both cell types, as well as tube formation of endothelial cells. Comparison with the angiogenesis inhibitors angiostatin and endostatin revealed similar results. Recombinant PRP-B is effective in promoting cell attachment of endothelial and smooth muscle cells, and antibody interference experiments reveal that the interaction of recombinant PRP-B with endothelial cells is mediated at least in part by alpha(v)-containing integrins. Inhibition of angiogenesis in vivo by PRP-B was demonstrated in the chicken chorioallantoic membrane assay. PRP-B and other antiangiogenic molecules may elicit metabolic perturbations in endothelial cells as well as perivascular mesenchymal cells such as smooth muscle cells and pericytes.
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PMID:Interaction of plasminogen-related protein B with endothelial and smooth muscle cells in vitro. 1279 92

Endostatin is a fragment of collagen XVIII that acts as an inhibitor of tumor angiogenesis and tumor growth. Anti-tumor effects have been described using both soluble and insoluble recombinant endostatin. However, differences in endostatin structure are likely to cause differences in bioactivity. In the present study, we have investigated the cellular effects of insoluble endostatin. We previously found that insoluble endostatin shows all the hallmarks of amyloid aggregates and potently stimulates tissue plasminogen activator-mediated formation of the serine protease plasmin. We here show that amyloid endostatin induces plasminogen activation by endothelial cells, resulting in vitronectin degradation and plasmin-dependent endothelial cell detachment. Endostatin-mediated stimulation of plasminogen activation, vitronectin degradation, and endothelial cell detachment is inhibited by carboxypeptidase B, indicating an essential role for carboxyl-terminal lysines. Our results suggest that amyloid endostatin may inhibit angiogenesis and tumor growth by stimulating the fibrinolytic system.
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PMID:Amyloid endostatin induces endothelial cell detachment by stimulation of the plasminogen activation system. 1280 3

Tumor growth, local invasion, and metastatic dissemination are dependent on the formation of new microvessels. The process of angiogenesis is regulated by a balance between pro-angiogenic and anti-angiogenic factors, and the shift to an angiogenic phenotype (the "angiogenic switch") is a key event in tumor progression. The use of anti-angiogenic agents to restore this balance represents a promising approach to cancer treatment. Known physiological inhibitors include trombospondin, several interleukins, and the proteolytic break-down products of several proteins. Angiostatin, an internal fragment of plasminogen, is one of the more potent of this latter class of angiogenesis inhibitors. Like endostatin, another anti-angiogenic peptide derived from collagen XVIII, angiostatin can induce tumor vasculature regression, leading to a complete cessation of tumor growth. Inhibitors of angiogenesis target normal endothelial cells, therefore the development of resistance to these drugs is unlikely. The efficacy of angiostatin has been demonstrated in animal models for many different types of solid tumors. Anti-angiogenic cancer therapy with angiostatin requires prolonged administration of the peptide. The production of the functional polypeptides is expensive and technical problems related to physical properties and purity are frequently encountered. Gene transfer represents an alternative method to deliver angiostatin. Gene therapy has the potential to produce the therapeutic agent in high concentrations in a local area for a sustained period, thereby avoiding the problems encountered with long-term administration of recombinant proteins, monoclonal antibodies, or anti-angiogenic drugs. In this review we compare the different gene therapy strategies that have been applied to angiostatin, with special regard to their ability to provide sufficient angiostatin at the target site.
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PMID:Inhibition of tumor angiogenesis by angiostatin: from recombinant protein to gene therapy. 1290 56

Naturally occurring angiogenesis inhibitors can inhibit different steps of the angiogenic process, such as endothelial cell migration. However, the mechanisms underlying this inhibition have not been elucidated. We demonstrate that migration of human umbilical vein endothelial cells induced by the potent endothelial cell chemoattractant sphingosine 1-phosphate is refractory to inhibition by well-characterized angiogenesis inhibitors such as endostatin and plasminogen-related protein-B. Our data support the contention that for effective blockage of tumor-induced angiogenesis, antagonists of both G protein-coupled receptor signaling and receptor tyrosine kinase signaling must be combined.
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PMID:Sphingosine 1-phosphate and cell migration: resistance to angiogenesis inhibitors. 1455 Feb 87

The plasminogen activator/plasmin system represents a key component of the proteolytic machinery underlying angiogenesis. In this work, we investigated the effect of Neovastat (AE-941), a naturally occurring multifunctional antiangiogenic agent that is currently in Phase III clinical trials, on tissue and urokinase plasminogen activator activities. We found that in vitro, Neovastat at 100 microg/ml markedly stimulates t-PA-mediated plasmin generation, while it slightly inhibits the generation of plasmin mediated by uPA. The stimulatory effect of Neovastat on t-PA activity was markedly increased by a heat treatment, resulting in a 15-fold increase in the rate of activation of plasminogen. Neovastat did not directly stimulate the activity of t-PA or plasmin towards exogenous substrates, suggesting that its effect requires the presence of plasminogen. Accordingly, kinetic analysis showed that Neovastat increases both the k(cat) of t-PA as well as its affinity for plasminogen by 10-fold. The stimulation of t-PA activity by Neovastat was also correlated with a direct interaction of Neovastat with plasminogen as monitored by the surface plasmon resonance technology. Overall, these results identify Neovastat as a potent stimulator of t-PA-dependent activation of plasminogen, further emphasizing its pleiotropic mechanism of action on several molecular events involved in angiogenesis.
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PMID:The antiangiogenic agent Neovastat (AE-941) stimulates tissue plasminogen activator activity. 1470 91


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