Fibrinolysis and Proteolysis最新文献

{"title":"A review of the expression, assembly, secretion and intracellular degradation of fibrinogen","authors":"C. Redman, H. Xia","doi":"10.1054/FIPR.2000.0069","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0069","url":null,"abstract":"Abstract The expression, assembly and secretion of fibrinogen are reviewed. Fibrinogen, the product of three exquisitely controlled genes, has a high basal level of expression and its production is further greatly increased in response to infection and/or tissue damage. In hepatocytes, the principal source of plasma fibrinogen, constitutive expression of the Aα and Bβ genes is mostly dependent on HNF-1 while the γ gene depends on at least three ubiquitous transcription factors. As a member of the acute phase proteins, fibrinogen expression is up-regulated by interleukin-6 (IL-6) and the glucocorticoids causing a coordinated expression of all three genes. IL-6 up-regulation of the fibrinogen genes involves activation of the STAT-3 and C/EBP transcription factors. Fibrinogen chain assembly occurs in the endoplasmic reticulum (ER) in a step-wise manner in which single chains form two-chain complexes (Aα-γ and Bβ-γ) which subsequently acquire a third chain to form a half-molecule. In a final step the two half-molecules are joined to form fibrinogen. Chain assembly is facilitated by chaperones and distinct structural domains of fibrinogen are necessary for proper assembly. Removal of the C-terminal half of the coiled coil region of the chains prevents chain assembly and disruption of the disulfide rings that flank the proximal N-terminal portion of the coiled-coil, or deletion of the N-terminal half of the coiled-coil, prevents half-molecules from forming dimers. Intracellular proteolysis plays a role in the regulation of fibrinogen chain assembly. Hepatocytes contain surplus Aα and γ chains and the ubiquitin-proteasome pathway is involved in degrading unassembled Bβ and γ chains. Aα-γ complexes are degraded by lysosomes.","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"44 1","pages":"198-205"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81602827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein C inhibitor (PAI-3): structure and multi-function","authors":"Koji Suzuki","doi":"10.1054/FIPR.2000.0063","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0063","url":null,"abstract":"Abstract Protein C inhibitor (PCI) is a member of the serine protease inhibitor (serpin) family, which was initially found to be an inhibitor of activated protein C (APC) and later a potent inhibitor of the thrombin-thrombomodulin complex, suggesting that PCI plays a pivotal role in the regulation of the anticoagulant protein C pathway in human plasma. PCI is also known as a plasminogen activator inhibitor-3 (PAI-3), since this serpin was found in urine forming a complex with urokinase type-plasminogen activator (uPA). Human PCI also inhibits several other serine proteases involved in blood coagulation and fibrinolysis. Precursor proteins of PCI deduced from human, rhesus monkey, bovine, rabbit, rats and mouse cDNAs have sequence homology from 62 to 93%. Human PCI gene is located in a region involving genes of related serpins in chromosome 14q32.1. As regulatory mechanism of PCI gene expression, Sp1- and AP2-binding sites in the 5′-flanking region are the promoter and the enhancer, respectively. PCI mRNA is expressed in many organs, such as liver, kidney, spleen, pancreas, and reproductive organs (including testis, prostate, seminal vesicles and ovary in humans) and also in the liver and reproductive organs in bovines and rabbits; though in rats and mice only in the reproductive organs. PCI appears to play a role in the regulation of fertilization, presumably by inhibiting prostate specific antigen and acrosin in the male reproductive organs or by inhibiting protease(s) in the ovaries. In addition to the roles of PCI in coagulation, fibrinolysis and fertilization, human PCI is also suggested to regulate wound healing and renal tumour metastasis by inhibiting hepatocyte growth factor activator and uPA, respectively. Thus, PCI is a unique multi-functional serpin member playing several roles depending on species and organ tissues.","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"60 1","pages":"133-145"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81291444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The urokinase plasminogen activator system as a novel target for tumour therapy","authors":"M. Schmitt, O. Wilhelm, U. Reuning, A. Krüger, N. Harbeck, E. Lengyel, H. Graeff, B. Gansbacher, H. Kessler, M. Bürgle, J. Stürzebecher, S. Sperl, V. Magdolen","doi":"10.1054/FIPR.2000.0079","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0079","url":null,"abstract":"Abstract Substantial data have been collected for numerous types of solid cancer, including cancer of the breast, the gastrointestinal and urological tract, the lung, and the brain, demonstrating a strong clinical value of the plasminogen activation system in predicting disease recurrence and survival in cancer patients. Elevated levels of certain members of the plasminogen activation system, the serine protease uPA (urokinase-type plasminogen activator), its receptor (uPA-R; CD87), and inhibitor (PAI-1), in tumour tissue or blood emphasize their fundamental role in tumour invasion and metastasis and provide the rationale for novel therapeutic strategies. uPA, besides its proteolytic action toward the extracellular matrix, in concert with uPA-R, PAI-1, and integrins contributes to tumour cell proliferation, adhesion, and migration. Several technical methods of affecting tumour growth and metastasis by targeting the uPA-system in cancer patients at the gene and protein level have been explored: (1) antisense oligodeoxynucleotides to uPA, uPA-R, or PAI-1; (2) antisense oligonucleotides to signal transduction pathway components such as Rel (NF-κ B), affecting uPA but not PAI-1 synthesis; (3) viral vectors delivering genes for components of the plasminogen activation system; (4) soluble, recombinant uPA-R as a scavenger for uPA; (5) monoclonal antibodies directed to uPA or uPA-R blocking uPA/uPA-R interaction; (6) enzymatically inactive uPA to compete for active uPA binding to uPA-R; (7) linear and cyclic uPA-derived peptides to block uPA/uPA-R interaction; (8) toxins, coupled to uPA or fractions thereof to kill tumour cells; (9) naturally occurring inhibitors to uPA and its derivatives for inhibition of uPA proteolytic activity; and (10) synthetic inhibitors to uPA to inhibit uPA proteolytic activity. There is substantial hope that substances designed to affect or turn off the plasminogen activation system will eventually be administered to cancer patients thereby opening a new vista for tumour biology-based, individualized cancer therapy.","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"12 1","pages":"114-132"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87291208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of fibrinolytic activity by localization of inhibitors to fibrin(ogen)","authors":"N. Booth","doi":"10.1054/FIPR.2000.0071","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0071","url":null,"abstract":"Abstract Fibrin plays a key role in fibrinolysis, acting not only as a substrate but also as a regulator of activity. As well as stimulating plasminogen activation, it controls interactions between proteases and inhibitors, both protecting proteases from inhibition and, conversely, localizing inhibitors. The principal inhibitor of plasmin, α2-antiplasmin, is cross-linked to fibrinogen and fibrin, inhibiting fibrinolysis. Our studies have shown that a second inhibitor, PAI-2, is also cross-linked to fibrinogen and fibrin, by either factor XIIIa or tissue transglutaminase. These inhibitors are both members of the serpin family but the cross-linking sites are quite unrelated. Cross-links are formed between glutamine residues in the inhibitors and lysine residues in fibrin(ogen). The Gln residues involved are at position 2 in the N-terminus of α2-AP and at position 83 and 86 in PAI-2, located in a loop between helices C and D. All cross-linking observed was to the Aα chain of fibrin(ogen). The two inhibitors did not compete for cross-linking sites. α2-AP binds only to Lys 303 of the Aα chain and a 30-residue peptide based on the sequence around this Lys competed with fibrinogen for cross-linking to α2-AP but not for cross-linking to PAI-2. PAI-2 was cross-linked to several Lys residues (but not Lys 303) in the Aα chain, as shown by tryptic digestion and mass spectrometry. PAI-2 was cross-linked to Lys 148, 176, 183 and 467 by tissue transglutaminase and to Lys 148, 176, 230 and 413 by factor XIIIa. The activity of PAI-2 was not affected by cross-linking, so that this is a mechanism whereby it can be covalently bound to fibrinogen and retained in a fibrin clot, without loss of activity towards u-PA and two-chain t-PA. PAI-1, the other major inhibitor of fibrinolysis, also binds to fibrin but we find no evidence for its being cross-linked. All three inhibitors achieve high local concentrations on fibrin, which they protect from lysis by t-PA, u-PA and plasmin. The inhibitors differ in their major sources in blood, with α2-AP present at high concentrations in plasma, PAI-1 primarily in platelets, and PAI-2 a product of stimulated monocytes, giving them distinct and complementary roles in stabilizing fibrin in different physiological and pathological locations.","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"18 1","pages":"206-213"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85508948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic polymorphisms associated with thrombotic disorders in the Japanese population","authors":"M. Murata","doi":"10.1054/FIPR.2000.0064","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0064","url":null,"abstract":"Abstract Genetic factors in combination with a number of environmental risk factors are involved in a predisposition to thrombotic disorders. Coronary artery disease (CAD) and ischemic cerebrovascular disease are typical human attributes that have a complex multifactorial etiology. There has been an increased awareness of the contribution of inherited factors for multifactorial disorders like thrombosis since the discovery of two prothrombotic mutations, the factor V Leiden and the prothrombin G20210A mutations, prevalent in Caucasian populations. Elevated plasma levels of homocysteine also constitute a risk factor for venous and arterial thrombosis. Thrombophilia is now thought to be common, not limited to rare conditions such as congenital deficiencies of the physiologic coagulation inhibitors. It has long been thought that Japan has a lower incidence of thrombotic diseases, although there are only small differences in the prevalence of antithrombin, protein C, or protein S deficiencies. There are, however, critical differences in the prevalence of common polymorphisms relevant to thrombosis. The factor V Leiden and prothrombin mutations are absent in the Japanese, and a polymorphism of a platelet integrin, the glycoprotein IIIa 33Leu/Pro, which has a controversial relationship with arterial thrombosis in Caucasian populations, is very rare in Japan. Also, allele frequencies of some clinically relevant factors are different, including platelets and blood coagulation factors. Thus, a separate study is needed for each population with a distinct ethnic background. In a number of allelic association studies involving patients with CAD, ischaemic stroke, peripheral artery disease, and vascular complications of diabetes, we found that the effect of genetic factors varied significantly depending on the characteristics of the cases and controls selected. A certain combination of multiple genetic risk factors was found to greatly increase the risk of stroke, particularly in young subjects. Many genes are involved in determining the inter-individual variation in traits that define the onset and progression of disease, as well as the response to treatment. No single gene is expected to have a major impact on the determination of the risk of thrombosis. The ultimate goal of the clinical appreciation of polymorphic markers is to identify subgroups of individuals in which the disease can be best prevented, or who respond best to interventions.","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"344 1","pages":"155-164"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79615610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current technologies in gene expression profiling: applications to cardiovascular research","authors":"S.van Soest, A.J.G. Horrevoets, N.J. Beauchamp, H. Pannekoek","doi":"10.1054/fipr.2000.0055","DOIUrl":"https://doi.org/10.1054/fipr.2000.0055","url":null,"abstract":"","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"14 2","pages":"Pages 73-81"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1054/fipr.2000.0055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71826161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor cell-mediated proteolysis: regulatory mechanisms and functional consequences","authors":"S. Ghosh,&nbsp;S.M. Ellerbroek,&nbsp;Y. Wu,&nbsp;M.S. Stack","doi":"10.1054/fipr.2000.0060","DOIUrl":"https://doi.org/10.1054/fipr.2000.0060","url":null,"abstract":"<div><p>The mammalian organism is composed of an inter-dependent series of tissue compartments separated from each other by an extracellular matrix (ECM). This ECM functions as both a determinant of tissue architecture and a mechanical barrier to cellular invasion. ECM proteolysis facilitates tissue penetration, and a distinctive property of many malignant tumor cells is the capacity to invade host tissues and establish metastatic foci. Malignant cells produce a spectrum of matrix-degrading proteinases with activities directed against the major ECM proteins. These enzymes are identical to those normally involved in physiologic processes; however, proteinase regulation is altered such that enzyme expression and/or activity are inappropriately controlled. The purpose of this review is to highlight biochemical mechanisms commonly utilized by tumor cells to regulate proteinase activity and to discuss the potential functional consequences with respect to tumor cell behavior. Specific examples will be provided to illustrate the concepts of regulation via limited proteolysis, enzyme-inhibitor binding, compartmentalization, and alteration of proteinase expression.</p></div>","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"14 2","pages":"Pages 87-97"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1054/fipr.2000.0060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71826233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular interactions between the plasminogen/plasmin and matrix metalloproteinase systems","authors":"H.R. Lijnen","doi":"10.1054/fipr.2000.0065","DOIUrl":"https://doi.org/10.1054/fipr.2000.0065","url":null,"abstract":"<div><p>Circumstantial evidence suggests an important role of the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems in biological processes involving (extra)cellular proteolysis and matrix degradation. The availability of mice with inactivation of main components of both systems has allowed to study directly the interactions between both systems and their biological role.</p><p>In purified system, MMP-3 (stromelysin-1) specifically hydrolyzes plasminogen and urokinase-type plasminogen activator (u-PA), thereby removing the cellular binding domains from both proteins. In the presence of cells, MMP-3 may downregulate cell-associated plasmin activity by decreasing the amount of activatible plasminogen, without affecting cell-bound u-PA activity.</p><p>During neointima formation after vascular injury in gene-deficient mice, expression of MMP-2 and MMP-9 (gelatinase A and B) is strongly enhanced, independently of the presence or absence of plasminogen or of the physiological plasminogen activators. Activation of proMMP-2 occurs independently of plasmin, whereas proMMP-9 activation occurs via plasmin-dependent as well as plasmin-independent mechanisms. The temporal and topographic expression patterns of MMP-2, MMP-3, MMP-9, MMP-12 (metalloelastase) and MMP-13 (collagenase) establish a potential role in neointima formation. This is further substantiated by the finding that neointima formation after vascular injury is significantly enhanced in mice with deficiency of TIMP-1, a main physiological MMP inhibitor.</p><p>Atherosclerosis models in gene-deficient mice suggest an important role of u-PA in the structural integrity of the atherosclerotic vessel wall. u-PA-mediated plasmin generation may contribute to activation of latent MMPs (MMP-3, -9, -12, and -13) which degrade insoluble elastin and fibrillar collagen.</p><p>Thus, studies with gene-deficient mice have allowed to establish novel interactions between the fibrinolytic and MMP systems, which may play a role in biological processes requiring cellular proteolytic activity and/or extracellular matrix degradation.</p></div>","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"14 2","pages":"Pages 175-181"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1054/fipr.2000.0065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71826234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging regulatory mechanisms for fibrinolytic gene expression","authors":"M. Koziczak,&nbsp;L. Montero,&nbsp;F. Maurer,&nbsp;Y. Nagamine","doi":"10.1054/fipr.2000.0053","DOIUrl":"https://doi.org/10.1054/fipr.2000.0053","url":null,"abstract":"<div><p>Fibrinolytic genes are involved in many biological processes, such as fibrinolysis, wound healing, inflammation and tumor metastasis, some of which rely on non-catalytic properties of the gene products. Reflecting the broad biological functions, expression of these genes is controlled by several mechanisms. Since the identification of fibrinolytic genes 2 decades ago, a vast amount of information has accumulated about the many signals, signaling pathways and mechanisms inducing their transcription. Our knowledge in this field is still expanding, and in this article we discuss two further emerging mechanisms by which expression of these genes is regulated: cell cycle-mediation and mRNA stability.</p></div>","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"14 2","pages":"Pages 146-154"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1054/fipr.2000.0053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71826240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular transport during fibrin clot lysis","authors":"D. Rijken, D. V. Sakharov","doi":"10.1054/FIPR.2000.0072","DOIUrl":"https://doi.org/10.1054/FIPR.2000.0072","url":null,"abstract":"Abstract Fibrin clot lysis is a dynamic process in which transport of fibrinolytic proteins plays an important role. Various recently established transport processes for plasminogen as well as for tissue-type and urokinase-type plasminogen activator (t-PA and u-PA, respectively) are reviewed. During internal lysis of a plasma clot, plasminogen is translocated from the fluid phase to the surface of the lysing fibrin fibres. During external lysis, plasminogen strongly accumulates on the moving surface of the clot. In both types of lysis, binding takes place on C-terminal lysine residues in partially degraded fibrin that are generated by plasmin. The recently discovered thrombin activatable fibrinolysis inhibitor (TAFI) inhibits plasminogen binding by removing the C-terminal lysine residues. TAFI is a plasma carboxypeptidase B that is activated by thrombin and that links the coagulation system and the fibrinolytic system. Transport of plasminogen activators is, in particular, essential for external clot lysis as it occurs during thrombolytic therapy. Because transport of proteins is not only mediated by diffusion, but also by fluid permeation, flow strongly promotes clot lysis. Penetration of plasminogen activators into clots is hampered by fibrin binding. While t-PA sticks to the surface of a clot, u-PA is able to enter a clot unhindered. Recent studies show that ultrasound promotes plasminogen activator-induced clot lysis. A variety of mechanisms have been proposed to explain this promotion. Results indicate that an increased transport of fibrinolytic proteins significantly contributes to the acceleration of fibrinolysis by ultrasound.","PeriodicalId":100526,"journal":{"name":"Fibrinolysis and Proteolysis","volume":"2 1","pages":"98-113"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84585785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}