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Irene Martínez-Martínez

Irene Martínez-Martínez
Instituto Murciano de Investigación Biosanitaria-IMIB Arrixaca · Centro Regional de Hemodonación

PhD in Biochemistry

About

94
Publications
7,820
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990
Citations
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January 2006 - December 2012
University of Murcia

Publications

Publications (94)
Article
Full-text available
Hepsin is a type II transmembrane serine protease whose deregulation promotes tumor invasion by proteolysis of the pericellular components. In colorectal cancer, the implication of hepsin is unknown. Consequently, we aimed to study the correlations between hepsin expression and different clinical-histopathological variables in 169 patients with loc...
Preprint
Background Hepsin is a type II transmembrane serine protease whose functions include degradation of the extracellular matrix and activation of factor VII. In many tumors, hepsin dysregulation leads to tumor invasion by proteolysis of pericellular components. Colorectal cancer is a tumor with high thrombotic and metastatic risk, but the role of heps...
Article
Full-text available
The endogenous protease furin is a key protein in many different diseases, such as cancer and infections. For this reason, a wide range of studies has focused on targeting furin from a therapeutic point of view. Our main objective consisted of identifying new compounds that could enlarge the furin inhibitor arsenal; secondarily, we assayed their ad...
Article
Full-text available
Advanced gastric cancer is one of the most thrombogenic neoplasms. However, genetic mechanisms underlying this complication remain obscure, and the molecular and histological heterogeneity of this neoplasm hinder the identification of thrombotic biomarkers. Therefore, our main objective was to identify genes related to thrombosis regardless of Laur...
Article
Introduction The mechanism of action of immune checkpoints inhibitors hinders the writing of rational statistical analysis plans for phase III randomised clinical trials (RCTs) because of their unpredictable dynamic effects. The purpose is to illustrate the advantages of Bayesian reporting of treatment efficacy analysis in immunotherapy RCTs, in co...
Article
Full-text available
Antithrombin, the main physiological inhibitor of the coagulation cascade, exerts anti-tumor effects on glioblastoma multiforme cells. Antithrombin has different conformations: native, heparin-activated, prelatent, latent, and cleaved. The prelatent form has an intermediate affinity between latent and native antithrombin, although it is the most an...
Article
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Exosomes are extracellular vesicles that contain nucleic acids, lipids and metabolites, and play a critical role in health and disease as mediators of intercellular communication. The majority of extracellular vesicles in the blood are platelet-derived. Compared to adults, neonatal platelets are hyporeactive and show impaired granule release, assoc...
Article
Full-text available
N-linked glycosylation is a crucial post-translational modification involved in protein folding, function, and clearance. N-linked glycosylation is also used therapeutically to enhance the half-lives of many proteins. Antithrombin, a serpin with four potential N-glycosylation sites, plays a pivotal role in hemostasis, wherein its deficiency signifi...
Article
Background: Hereditary antithrombin deficiency is a rare autosomal-dominant disorder predisposing to recurrent venous thromboembolism (VTE). To date, only two founder mutations have been described. Objectives: We investigated the antithrombin p.Thr147Ala variant, found in 12 patients of African origin. This variant is known as rs2227606 with min...
Article
Full-text available
Severe infectious diseases are often characterized by an overwhelming and unbalanced systemic immune response to microbial infections. Human antithrombin (hAT) is a crucial coagulation inhibitor with anti-inflammatory activities. Here we identify three hAT-binding proteins (CD13, CD300f and LRP-1) on human monocytes that are involved in blocking th...
Article
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Antithrombin is a serine protease inhibitor that exerts a crucial role in hemostasis as the main inhibitor of the coagulation cascade. It plays also critical roles in other processes, such as inflammation and cancer. Here we show that exosomes released by Madin-Darby canine kidney (MDCK) cells cultured in the presence of heparin incorporate antithr...
Article
Full-text available
SERine Protease INhibitorS (Serpins) are a superfamily of proteins that are characterized by having a similar three-dimensional structure. The native conformation is not most thermodynamically stable, so polymerization is the main consequence when its stability is altered as a result of certain mutations. The polymerization of serpins has been a re...
Article
Full-text available
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a clonal disease of blood cells caused by the lack of glycosyl phosphatidyl inositol anchored proteins bound to the cell membrane. In consequence, erythrocytes lead to intravascular hemolysis upon complement activation, which promotes high risk of thrombosis, intravascular hemolytic anemia, and bone marr...
Article
Full-text available
Antithrombin mainly inhibits factor Xa, and thrombin. The reactive center loop (RCL) is crucial for its interactions with its protease targets and is fully inserted into the A-sheet after its cleavage, causing translocation of the covalently linked protease to the opposite end of the A-sheet. Antithrombin variants with altered RCL hinge residues be...
Article
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Background: There is increasing evidence supporting the relevance of aberrant splicing in multiple disorders. In antithrombin deficiency only 22 intronic mutations affecting splicing sites (7% of SERPINC1 mutations) are considered as splicing mutations. Methods: SERPINC1 was analyzed by Sanger sequencing and MLPA in 141 unrelated cases with anti...
Conference Paper
Full-text available
Background: Mutations affecting splicing are getting more relevance in the development of multiple human genetic diseases. In antithrombin (AT) deficiency only 17 mutations affecting intron splicing signals (IVS) have been described (5.8% of mutations identified in SERPINC1), all resulting in type I deficiency without variant AT in plasma. Aims: To...
Article
Full-text available
Heparanase is an endoglycosidase that participates in morphogenesis, tissue repair, heparan sulphates turnover and immune response processes. It is over-expressed in tumor cells favoring the metastasis as it penetrates the endothelial layer that lines blood vessels and facilitates the metastasis by degradation of heparan sulphate proteoglycans of t...
Data
Intrinsic fluorescence change in antithrombin caused by heparanase titration. Black dots represent the conformational activation of antithrombin (+AT). White dots represent the fluorescence of the heparanase added during the titration (-AT). (TIF)
Data
Absence of the Histidine-tag and TFPI in the heparanase preparation. SDS-PAGE under reducing conditions and western blot of heparanase sample for immunodetection of the Histidine-tag (left panel) or TFPI (right panel). Antithrombin with a histidine-tag at C-terminal (AT-His) was used as control for the histidine immunodetection (20 ng), to compare...
Data
Proheparanase expression in the supernatant of 293T cells and effect on the activation of antithrombin. A) Proheparanase expression on the conditioned medium of 293 cells transfected with a plasmid expressing proheparanase Myc-DDK-tagged and an empty plasmid (Mock) was assayed by Western Blot using an anti-c-Myc antibody after SDS-PAGE under reduci...
Article
Full-text available
Bleeding is a relatively common complication in patients with multiple myeloma. Different factors have been involved, like heparin-like anticoagulants, although the underlying mechanism remains obscure. The identification of a patient with a quiescent multiple myeloma IgG- that suffered severe bleeding event controlled by rFVIIa and had prolonged...
Article
Full-text available
Antithrombin is a key inhibitor of the coagulation cascade, but it may also function as an anti-inflammatory, anti-angiogenic, anti-viral and anti-apoptotic protein. Here, we report a novel function of antithrombin as a modulator of tumor cell migration and invasion. Antithrombin inhibited enteropeptidase on the membrane surface of HT-29, A549 and...
Article
Background: Since the discovery of antithrombin deficiency, 50 years ago, few new thrombophilic defects have been identified, all with weaker risk of thrombosis than antithrombin deficiency. Objective: To identify new thrombophilic mechanisms. Patients/methods: We studied 30 patients with antithrombin deficiency but no defects in the gene enco...
Article
The key haemostatic role of antithrombin and the risk of thrombosis associated with its deficiency support that the low incidence of antithrombin deficiency among patients with thrombosis might be explained by underestimation of this disorder. It was our aim to identify mutations in SERPINC1 causing transient antithrombin deficiency. SERPINC1 was s...
Article
β-antithrombin, the minor antithrombin glycoform in plasma, is probably the major thrombin inhibitor in vivo because of its high heparin affinity. The levels and variability of this glycoform in general population and its relevance in thromboembolic diseases is unknown since there is no specific method to measure this glycoform in clinical samples....
Article
Full-text available
Platelet cold agglutinins (PCA) cause pseudothrombocytopenia, spurious thrombocytopenia due to ex vivo platelet clumping, complicating clinical diagnosis, but mechanisms and consequences of PCA are not well defined. Here, we characterised an atypical immunoglobulin (Ig)M PCA in a 37-year-old woman with lifelong bleeding and chronic moderate thrombo...
Article
Full-text available
The inefficient glycosylation of consensus sequence on N135 in antithrombin explains the two glycoforms of this key anticoagulant serpin found in plasma: α and β, with four and three N-glycans, respectively. The lack of this N-glycan increases the heparin affinity of the β-glycoform. Recent studies have demonstrated that an aromatic sequon (Phe-Y-A...
Article
Background The characterization of natural mutants identified in patients with antithrombin deficiency has helped to identify functional domains or regions of this key anticoagulant, the mechanisms involved in the deficiency as well as to define the clinical prognosis. Recently, we described an abnormal glycosylation in a pleiotropic mutant (K241E)...
Article
Full-text available
Mutations in PMM2 impair phosphomannomutase-2 activity and cause the most frequent congenital disorder of glycosylation, PMM2-CDG. Mannose-1-phosphate, that is deficient in this disorder, is also implicated in the biosynthesis of glycosylphosphatidyl inositol (GPI) anchors. To evaluate whether GPI-anchor and GPI-anchored proteins are defective in P...
Article
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Oviduct fluid increases the time required for digestion of the zona pellucida (ZP) by protelolytic enzymes (ZP hardening). This effect has been associated to the levels of monospermy after fertilization in vitro (IVF) in the pig and cow but the possible existence of a directly proportional relation between hardening and monospermy remains unknown....
Article
Full-text available
The haemostatic relevance of antithrombin together with the low genetic variability of SERPINC1, and the high heritability of plasma levels encourage the search for modulating genes. We used a hypothesis-free approach to identify these genes, evaluating associations between plasma antithrombin and 307,984 polymorphisms in the GAIT study (352 indivi...
Data
TaqMan® probes used for genotyping in the validation study. (DOCX)
Article
Full-text available
Background Developmental haemostatic studies may help identifying new elements involved in the control of key haemostatic proteins like antithrombin, the most relevant endogenous anticoagulant. Results In this study, we showed a significant reduction of sialic acid content in neonatal antithrombin compared with adult antithrombin in mice. mRNA lev...
Article
Antithrombin deficiency was the first congenital thrombophilic factor identified [1]. Since then, protein C and protein S deficiencies, as well as specific mutations in the factor V and prothrombin genes, have joined antithrombin deficiency as genetic defects predisposing patients to venous thrombosis. However, it is unlikely that new common polymo...
Article
The metastable native conformation of serpins is required for their protease inhibition mechanism, but also renders them vulnerable to missense mutations that promote protein misfolding with pathological consequences. To characterize the first antithrombin deficiency caused by a large in-frame insertion. Functional, biochemical and molecular analys...
Article
The medical and socioeconomic relevance of thromboembolic disorders promotes an ongoing effort to develop new anticoagulants. Heparin is widely used as activator of antithrombin but incurs side effects. We screened a large database in silico to find alternative molecules and predicted d-myo-inositol 3,4,5,6-tetrakisphosphate (TMI) to strongly inter...
Article
Coagulopathy caused by an imbalance of hemostatic factors is associated with the pathophysiology of liver disease. We have investigated the role of antithrombin (AT), a key anticoagulant serpin, in the onset of liver disease. Liver injury was induced by CCl(4) injection and bile duct ligation (BDL) in wild type (WT) and AT-deficient (AT(+/-)) mice....
Article
Full-text available
The balance between actions of procoagulant and anticoagulant factors protects organisms from bleeding and thrombosis. Thus, antithrombin deficiency increases the risk of thrombosis, and complete quantitative deficiency results in intrauterine lethality. However, patients homozygous for L99F or R47C antithrombin mutations are viable. These mutation...
Article
Full-text available
Mutations affecting mobile domains of antithrombin induce conformational instability resulting in protein polymerization that associates with a severe clinical phenotype, probably by an unknown gain of function. By homology with other conformational diseases, we speculated that these variants might infect wild-type (WT) monomers reducing the antico...
Article
Antithrombin is the main endogenous anticoagulant. Impaired function or deficiency of this molecule significantly increases the risk of thrombosis. We studied the genetic variability of SERPINC1 , the gene encoding antithrombin, to identify mutations affecting regulatory regions with functional effect on its levels. We sequenced 15,375 bp of this g...
Article
Background: Tissue factor (TF) is the main initiator of the coagulation cascade and elements that may upregulate its expression might provoke thrombotic events. Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are autoimmune diseases characterized by a high TF expression in monocytes. Objectives: To examine the role of micr...
Article
Full-text available
MicroRNAs (miRNAs) are an abundant class of small non-coding RNAs that are negative regulators in a crescent number of physiological and pathological processes. However, their role in haemostasis, a complex physiological process involving multitude of effectors, is just beginning to be characterized. We evaluated the changes of expression of miRNAs...
Article
Full-text available
β1-tubulin is the main constituent of the platelet marginal band and studies with deficient mice showed that it maintains discoid shape and it is required for normal platelet formation. TUBB1 Q43P polymorphism is associated with decreased β1-tubulin expression, diminished platelet reactivity, and partial loss of discoid shape in heterozygous carrie...
Article
Factor VIIa (FVIIa), a trypsin-like serine protease, plays an essential role in haemostasis by initiating the coagulation in complex with its cofactor, tissue factor (TF). The TF pathway inhibitor is the main physiological inhibitor of FVIIa-TF complex, but FVIIa can also be inhibited by antithrombin, although little is known about this process. Fu...