Disease relevance of F2

• Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice [1].
• Using this knowledge, we generated influenza viruses knocked out for the expression of PB1-F2 protein and its downstream truncation products [1].
• BACKGROUND: G to A mutations at positions 20210 of the prothrombin gene (F2) and 1691 of the factor V gene (F5) are established risk factors for venous thrombosis [2].
• Several factors associated with coagulation and/or fibrinolysis have been associated with arterial occlusive disease, but the role of F2 20210A and F5 1691A for arterial occlusive disease remains unclear [2].
• METHODS AND RESULTS: We analyzed the prevalence of F2 20210A and F5 1691A alleles in 336 patients with documented PAOD at Fontaine stage II-IV and 300 controls without vascular disease [2].
• Higher plasma prothrombin levels in carriers of prothrombin 19911 A > G polymorphism than in non-carriers were found among individuals without thrombophilia (P =0.05) and with FV Leiden (P = 0.07), but not in carriers of prothrombin 20210 GA (P = 0.2) [3].
• The FIIA19911G polymorphism is associated with mildly elevated prothrombin activity and is a risk factor for venous thrombosis [4].
• Isolated symptomatic PE was less prevalent in patients with FV Leiden (6%) than in those with prothrombin G20210A (21%) and no thrombophilia (23%) (P > 0.0001) [5].

High impact information on F2

• Enhanced mRNA 3' end formation efficiency emerges as a novel principle causing a genetic disorder and explains the role of the F2 20210 G-->A mutation in the pathogenesis of thrombophilia [6].
• gamma-Carboxyglutamic acid residues on prothrombin are synthesized from glutamic acid on a prothrombin precursor in the liver through a vitamin K-dependent carboxylase [7].
• There were higher levels of F2 mRNA (encoding prothrombin) as well as prothrombin and thrombin protein in liver of C3-/- mice compared to C3+/+ mice [8].
• Prostaglandins A1, A2, B1, B2, E2, F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2, which do not affect platelet cyclic AMP level, did not stimulate the protease [9].
• These data suggest that reduced synthesis as well as impaired carboxylation of prothrombin precursor protein are factors contributing to the coagulopathy in patients with moderate to severe liver disease and that measurement of circulating levels of II-Ag may provide an excellent indication of hepatic synthetic capacity [10].

Biological context of F2

• F2 20221(*)T thus represents the first example of a likely pathologically relevant mutation of the putative CstF binding site in the 3'flanking sequence of a human gene [11].
• Kringle F2 binds to thrombin at the heparin binding site through charge complementarity; a conformational change appears to occur on binding [12].
• In addition, the cDNA probe for F2 recognizes a homologous sequence which has been tentatively mapped to the X chromosome [13].
• Knocking out the PB1-F2 protein had no effect on viral replication in tissue culture but diminished virus pathogenicity and mortality in mice [1].
• The influenza virus PB1-F2 protein is a novel protein previously shown to be involved in induction of cell death [1].

Anatomical context of F2

• The gene for human prothrombin, or factor II (F2) has been assigned to 11p11-q12 by the combined use of a panel of somatic cell hybrid DNAs and in situ hybridization, using both cDNA and genomic probes [13].
• A survival assay of F2 cells from a mouse vascular endothelial cell line was performed in the presence of 10% pericardial fluid from each patient [14].
• Because the levels of coagulation factor II were not reduced in diabetic patients, the reduction of protein C seems to be caused, not by reduced synthesis in the liver, but more likely by an increased clearance from the blood plasma [15].
• Biologically active form of coagulation factor II, prothrombin could be synthesized and secreted into medium by immobilized hepatocytes [16].
• The PB1-F2 protein of Influenza A virus: increasing pathogenicity by disrupting alveolar macrophages [17].

Associations of F2 with chemical compounds

• Finally, we show that the low-efficiency F2 cleavage and CstF binding sites are balanced by a stimulatory upstream uridine-rich element in the 3'UTR [11].
• PA (after stimulation with ADP), P-selectin expression and fibrinogen binding to glycoprotein (GP) IIb/IIIa (determined by flow cytometry with and without stimulation with ADP), and levels of soluble P-selectin, prothrombin fragments F1 and F2, thrombin-antithrombin complexes (TAT), and antithrombin III (ATIII) were determined [18].
• This serine protease was detected by measuring the concentrations of activation fragments (F2/F1+2) cleaved from prothrombin [19].
• The immunologic expression of this area is unaffected by denaturation or reduction-alkylation of F2 as well as by attachment of polypeptide to the NH2-terminal of this component [20].
• Acclimation of wild type and the chlorina F2 mutant of barley to either high light or low temperature results in a 2- to 3-fold increase in non-photochemical quenching which occurred independently of either energy-dependent quenching (qE), xanthophyll cycle-mediated antenna quenching or state transitions [21].

Physical interactions of F2

• Monoclonal antibodies against F2 are superior to F4 or F1 antibodies as inhibitors of HK binding to FXI [22].

Other interactions of F2

• A chimeric FXI molecule in which F2 is replaced by P2 is cleaved within P2 during activation by factor XIIa, resulting in greatly reduced HK binding capacity [22].
• The order of affinity from highest to lowest is F2 F4 > F1 F3 [22].
• We successfully applied SNPicker in designing endonuclease restriction assays for 14 SNPs for the MTHFR gene, the Coagulation Factor II gene and the Coagulation Factor V gene [23].
• FMF (MEFV), factor V (F5), and factor II (F2) genotypes identified using this improved system were totally concordant with results of other genotyping methods (denaturing gradient gel electrophoresis [DGGE], SSCP, and RFLP analysis) [24].
• Fifteen men undergoing extracorporeal circulation for aorta-coronary bypass grafting were investigated for alterations of the plasma levels of cross-linked fibrin degradation products, protein C, free protein S, coagulation factor II, immunoglobulin G, and albumin [25].

Analytical, diagnostic and therapeutic context of F2

• The primary objective of this study was to apply a sophisticated coagulation monitoring system including estimation of the concentration of prothrombin fragment 1 + 2 (PTF 1 + 2) and the activity of prothrombin (coagulation factor II or FII) to cases of stent implantation and to compare the results with those of standard coagulation tests [26].
• A 97-bp DNA sequence of the coagulation factor V gene is co-amplified with a 111-bp DNA sequence of the coagulation factor II (PT) gene using four PCR primers [27].
• The levels of F2/F1+2) were quantitated by means of a sensitive and specific radioimmunoassay [19].
• To investigate the process of the abnormal prothrombin synthesis, the amount of prothrombin precursor was measured with an enzyme-linked immunosorbent assay using a specific antibody directed to human prothrombin; the vitamin-K-dependent gamma-carboxylation of prothrombin precursor was determined in human liver tissues [28].
• Polymorphisms in the genes for coagulation factor II, V, VII in patients undergoing coronary angiography [29].

References