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

Fetal mouse metatarsals are well-known models to study cartilage differentiation and osteoclastic resorption. We show here the outgrowth of PECAM-1 positive tubelike structures from the bone rudiments. This feature can be used to study angiogenesis in vitro. The area of outgrowth significantly increased with culture time, as shown by computerized image analysis of PECAM-1 positive tubelike structures. Treatment with recombinant human vascular endothelial growth factor (rhVEGF-A) stimulated the formation of tubelike structures. Treatment of explants with the angiogenesis inhibitor endostatin, the chemokine IP-10, and the thalidomide derivative phatolyl glutamic acid (PG-acid) resulted in an inhibition of the formation of PECAM-1 positive tubelike structures of 48.8% (+/- 4%), 50.2% (+/- 12%), and 80.8% (+/- 3%), respectively. Outgrowth of tubelike structures was partly dependent on endogenous VEGF-A because treatment with anti-mVEGF-A and truncated VEGF receptor 1 (soluble fms-like tyrosine kinase 1, sFIt1) strongly inhibited the formation of tubelike structures 74% (+/- 4%) and 38% (+/- 5%), respectively. Neither onset of tube formation nor total area of tubelike structures were changed when metatarsals were cultured on a fibrin gel or collagen type I gel. Tube formation required activation of matrix metalloproteinases because treatment of the bones with an inhibitor of matrix metalloproteinases completely inhibited migration and tube formation, whereas treatment with an inhibitor of plasmin had no effect. In conclusion, we describe a new in vitro model to study angiogenesis that can be used to test the angiogenic or antiangiogenic potential of novel test compounds that also combines the multicellularity of in vivo assays with the accessibility and flexibility of in vitro assays.
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PMID:Effect of angiogenic and antiangiogenic compounds on the outgrowth of capillary structures from fetal mouse bone explants. 1120 73

Extracellular proteolysis is an absolute requirement for new blood vessel formation, a process known as angiogenesis. This review will examine the role of the matrix metalloproteinase and plasminogen activator/plasmin systems during angiogenesis. Extracellular proteolysis has also been implicated in the generation of molecules with angioregulatory activity. These include, but are not limited to, angiostatin and endostatin. However, despite an abundance of data on their bioactivity, the molecular mechanisms by which these molecules achieve their effects are unknown. Anti-proteolysis, particularly in the context of angiogenesis, has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization.
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PMID:Extracellular proteolysis and angiogenesis. 1148 24

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

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

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

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

Angiogenesis refers to the formation of new blood vessels from an existing vasculature and is recognised as a necessary requirement for most tumours to grow beyond 1-2 mm in diameter. Factors established as playing a role in angiogenesis may be divided into two principal groups: (a) those that stimulate endothelial cell proliferation and/or elongation, migration and vascular morphogenesis including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet derived endothelial cell growth factor (PD-ECGF) and the tie and tek receptors, and (b) proteases and their receptors involved in the breakdown of basement membranes and the extracellular matrix (ECM) including the matrix metalloproteinases (MMPs), cathepsins and those involved in the plasmin cascade. Angiogenesis has been identified as a potential target for development of anticancer agents. The discovery of a range of naturally-occurring factors which negatively regulate angiogenesis, including the thrombospondins, angiostatin and endostatin, and the tissue inhibitors of MMPs (TIMPs), has given added impetus to this approach. Synthetic anti-angiogenic compounds have been developed, including TNP-470, carboxyamidotriazole, VEGF-tyrosine kinase inhibitors and MMP inhibitors (MMPI) which, like the naturally-occurring anti-angiogenic factors, inhibit angiogenesis in vitro and in vivo, and tumour development, growth and metastasis in vivo. Anti-angiogenic agents also enhance the antitumour activity of many conventional cytotoxic chemotherapeutic agents. Such combinations may have a particular role as adjuvant therapies following surgical resection of primary tumours. Unlike tumour cells, tumour associated endothelial cells do not develop resistance to anti-angiogenic agents. Furthermore, anti-angiogenic agents are generally cytostatic rather than cytotoxic. As such, these agents are, in general, likely to be administered over long periods of time. Therefore, as well as having proven antitumour efficacy, an anti-angiogenic compound will need to be well-tolerated if it is to become established in the clinical management of patients with malignant disease.
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PMID:Tumour angiogenesis: a novel therapeutic target in patients with malignant disease. 1598 2

The spirochete Leptospira interrogans is a highly invasive pathogen of worldwide public health importance. Studies from our laboratories and another have demonstrated that L. interrogans can acquire host plasminogen on its surface. Exogenous plasminogen activators can then convert bound plasminogen into the functionally active protease plasmin. In this study, we extend upon those observations and report that leptospiral endostatin-like protein A (LenA) binds human plasminogen in a dose-dependent manner. LenA-plasminogen interactions were significantly inhibited by the lysine analog xi-aminocaproic acid, suggesting that the lysine-binding sites on the amino-terminal kringle portion of the plasminogen molecule play a role in the binding. Previous studies have shown that LenA also binds complement regulator factor H and the extracellular matrix component laminin. Plasminogen competed with both factor H and laminin for binding to LenA, which suggests overlapping ligand-binding sites on the bacterial receptor. Finally, LenA-bound plasminogen could be converted to plasmin, which in turn degraded fibrinogen, suggesting that acquisition of host-derived plasmin by LenA may aid bacterial dissemination throughout host tissues.
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PMID:Leptospiral endostatin-like protein A is a bacterial cell surface receptor for human plasminogen. 2016 16