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Gene Review

Serpinc1  -  serine (or cysteine) peptidase inhibitor,...

Mus musculus

Synonyms: AI114908, ATIII, Antithrombin-III, At-3, At3, ...
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Disease relevance of Serpinc1


High impact information on Serpinc1


Chemical compound and disease context of Serpinc1


Biological context of Serpinc1

  • The data indicate the following gene order: (centromere)-CD45-6.5 cM-Lamb-2-1 cM-Abll-2 cM-At-3 [12].
  • This severe thrombotic phenotype underlines a critical function of the heparin-binding site of antithrombin and its interaction with heparin/heparan-sulfate moieties in health, reproduction, and survival, and represents an in vivo model for comparative analysis of heparin-derived and other antithrombotic molecules [7].
  • At doses of rhs-TM and heparin which were equally effective at inhibiting the decrease in platelet count and fibrinogen level in control rats treated with TF, only rhs-TM remained effective in preventing DIC in rats with reduced ATIII levels [3].
  • As a demonstration of the technique, a 5-cM, > 5 megabase contig was developed on the distal half of mouse Chromosome (Chr) 1, spanning the region from Lamb2 to At3 [13].
  • Antiangiogenic effects of latent antithrombin through perturbed cell-matrix interactions and apoptosis of endothelial cells [14].

Anatomical context of Serpinc1


Associations of Serpinc1 with chemical compounds

  • Antithrombin (AT) inhibits thrombin and some other coagulation factors in a reaction that is dramatically accelerated by binding of a pentasaccharide sequence present in heparin/heparan-sulfate to a heparin-binding site on AT [7].
  • Dansylarginine-N-(3-ethyl-1,5-pentanediyl)amide, a highly specific, potent antithrombin antagonist, inhibits LoVo-, HCT-8-, and Hut-20-induced platelet aggregation at 4 to 15 microM, whereas its effect on SV3T3 cells is negligible [18].
  • LTA cells synthesize a minor population of heparan sulfate proteoglycans (HSPGact) bearing anticoagulant heparan sulfate (HSact) with a specific monosaccharide sequence that accelerates the action of antithrombin (AT) [19].
  • A high proportion of antithrombin-binding sequence was also indicated by the finding that 3-O-sulfated glucosamine residues accounted for about 10% of the total O-sulfate groups [16].
  • The polysaccharide produced in the presence of butyrate showed a lower charge density on anion exchange chromatography than did the control material and a 3-fold increased proportion (54 versus 17% for the control) of components with high affinity for antithrombin [20].

Physical interactions of Serpinc1


Regulatory relationships of Serpinc1


Other interactions of Serpinc1

  • In the middle phase, increases in the activity of antithrombin III (ATIII) and alpha 2-plasmin inhibitor (alpha 2-Pl) followed [23].
  • The predicted reactive site (P1-P1') of this J6 protein is Arg-Ser, which is the same as that of antithrombin III [24].
  • These findings suggest that thrombin plays a key role in post-injury neuronal survival, and that its post-traumatic toxicity can be down-regulated by appropriate alteration of the amounts of PAR-1 receptors or of antithrombin III, the latter achieved by T cell-mediated autoimmunity [25].
  • It is proposed that the acidic domain interacts with thrombin at the protein C activation site and that this interaction is a prerequisite to the expression of direct as well as antithrombin-dependent anticoagulant activity [26].
  • An imbalance between thrombin and antithrombin III contributed to vascular hyporeactivity in sepsis, which can be attributed to excess NO production by inducible nitric-oxide synthase (iNOS) [27].

Analytical, diagnostic and therapeutic context of Serpinc1


  1. Complete antithrombin deficiency in mice results in embryonic lethality. Ishiguro, K., Kojima, T., Kadomatsu, K., Nakayama, Y., Takagi, A., Suzuki, M., Takeda, N., Ito, M., Yamamoto, K., Matsushita, T., Kusugami, K., Muramatsu, T., Saito, H. J. Clin. Invest. (2000) [Pubmed]
  2. Impact of antithrombin deficiency in thrombogenesis: lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin-deficient mice. Yanada, M., Kojima, T., Ishiguro, K., Nakayama, Y., Yamamoto, K., Matsushita, T., Kadomatsu, K., Nishimura, M., Muramatsu, T., Saito, H. Blood (2002) [Pubmed]
  3. Effects of recombinant human soluble thrombomodulin (rhs-TM) on a rat model of disseminated intravascular coagulation with decreased levels of plasma antithrombin III. Aoki, Y., Ohishi, R., Takei, R., Matsuzaki, O., Mohri, M., Saitoh, K., Gomi, K., Sugihara, T., Kiyota, T., Yamamoto, S. Thromb. Haemost. (1994) [Pubmed]
  4. Antithrombin reduces reperfusion-induced hepatic metastasis of colon cancer cells. Kurata, M., Okajima, K., Kawamoto, T., Uchiba, M., Ohkohchi, N. World J. Gastroenterol. (2006) [Pubmed]
  5. Generation of C5a in the absence of C3: a new complement activation pathway. Huber-Lang, M., Sarma, J.V., Zetoune, F.S., Rittirsch, D., Neff, T.A., McGuire, S.R., Lambris, J.D., Warner, R.L., Flierl, M.A., Hoesel, L.M., Gebhard, F., Younger, J.G., Drouin, S.M., Wetsel, R.A., Ward, P.A. Nat. Med. (2006) [Pubmed]
  6. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. Wahrenbrock, M., Borsig, L., Le, D., Varki, N., Varki, A. J. Clin. Invest. (2003) [Pubmed]
  7. Life-threatening thrombosis in mice with targeted Arg48-to-Cys mutation of the heparin-binding domain of antithrombin. Dewerchin, M., Hérault, J.P., Wallays, G., Petitou, M., Schaeffer, P., Millet, L., Weitz, J.I., Moons, L., Collen, D., Carmeliet, P., Herbert, J.M. Circ. Res. (2003) [Pubmed]
  8. Heparan sulfate 3-O-sulfotransferase isoform 5 generates both an antithrombin-binding site and an entry receptor for herpes simplex virus, type 1. Xia, G., Chen, J., Tiwari, V., Ju, W., Li, J.P., Malmstrom, A., Shukla, D., Liu, J. J. Biol. Chem. (2002) [Pubmed]
  9. Antiphospholipid antibodies: origin, specificity, and mechanism of action. Brey, R.L., Coull, B.M. Stroke (1992) [Pubmed]
  10. Coagulation disorders in experimentally induced acute mouse malaria. Reiner, G., Clemens, R., Bock, H.L., Enders, B. Acta Trop. (1991) [Pubmed]
  11. Low molecular weight protamine: a potential nontoxic heparin antagonist. Byun, Y., Singh, V.K., Yang, V.C. Thromb. Res. (1999) [Pubmed]
  12. Mapping of Abll within a conserved linkage group on distal mouse chromosome 1 syntenic with human chromosome 1 using an interspecific cross. Seldin, M.F., Kruh, G.D. Genomics (1989) [Pubmed]
  13. Rapid and efficient construction of yeast artificial chromosome contigs in the mouse genome with interspersed repetitive sequence PCR (IRS-PCR): generation of a 5-cM, > 5 megabase contig on mouse chromosome 1. Hunter, K.W., Ontiveros, S.D., Watson, M.L., Stanton, V.P., Gutierrez, P., Bhat, D., Rochelle, J., Graw, S., Ton, C., Schalling, M. Mamm. Genome (1994) [Pubmed]
  14. Antiangiogenic effects of latent antithrombin through perturbed cell-matrix interactions and apoptosis of endothelial cells. Larsson, H., Sjöblom, T., Dixelius, J., Ostman, A., Ylinenjärvi, K., Björk, I., Claesson-Welsh, L. Cancer Res. (2000) [Pubmed]
  15. L-asparaginase-induced antithrombin type I deficiency: implications for conformational diseases. Hernández-Espinosa, D., Miñano, A., Martínez, C., Pérez-Ceballos, E., Heras, I., Fuster, J.L., Vicente, V., Corral, J. Am. J. Pathol. (2006) [Pubmed]
  16. Structure and affinity for antithrombin of heparan sulfate chains derived from basement membrane proteoglycans. Pejler, G., Bäckström, G., Lindahl, U., Paulsson, M., Dziadek, M., Fujiwara, S., Timpl, R. J. Biol. Chem. (1987) [Pubmed]
  17. Biosynthesis of heparin. Availability of glucosaminyl 3-O-sulfation sites. Kusche, M., Torri, G., Casu, B., Lindahl, U. J. Biol. Chem. (1990) [Pubmed]
  18. Inhibition of the platelet-aggregating activity of two human adenocarcinomas of the colon and an anaplastic murine tumor with a specific thrombin inhibitor, dansylarginine N-(3-ethyl-1,5-pentanediyl)amide. Pearlstein, E., Ambrogio, C., Gasic, G., Karpatkin, S. Cancer Res. (1981) [Pubmed]
  19. Cell-free synthesis of anticoagulant heparan sulfate reveals a limiting converting activity that modifies an excess precursor pool. Shworak, N.W., Fritze, L.M., Liu, J., Butler, L.D., Rosenberg, R.D. J. Biol. Chem. (1996) [Pubmed]
  20. Biosynthesis of heparin. Effects of n-butyrate on cultured mast cells. Jacobsson, K.G., Riesenfeld, J., Lindahl, U. J. Biol. Chem. (1985) [Pubmed]
  21. Thrombin stimulates syndecan-1 promotor activity and expression of a form of syndecan-1 that binds antithrombin III in vascular smooth muscle cells. Cizmeci-Smith, G., Carey, D.J. Arterioscler. Thromb. Vasc. Biol. (1997) [Pubmed]
  22. Regulation of mouse T cell associated serine proteinase-1 (MTSP-1) by proteinase inhibitors and sulfated polysaccharides. Simon, M.M., Tran, T., Fruth, U., Gurwitz, D., Kramer, M.D. Biol. Chem. Hoppe-Seyler (1990) [Pubmed]
  23. Age-related changes in blood coagulation and fibrinolysis in mice fed on a high-cholesterol diet. Okazaki, M., Morio, Y., Iwai, S., Miyamoto, K., Sakamoto, H., Imai, K., Oguchi, K. Exp. Anim. (1998) [Pubmed]
  24. A retinoic acid-inducible mRNA from F9 teratocarcinoma cells encodes a novel protease inhibitor homologue. Wang, S.Y., Gudas, L.J. J. Biol. Chem. (1990) [Pubmed]
  25. T cell-mediated neuroprotection involves antithrombin activity. Friedmann, I., Hauben, E., Yoles, E., Kardash, L., Schwartz, M. J. Neuroimmunol. (2001) [Pubmed]
  26. Relationship between anticoagulant activities and polyanionic properties of rabbit thrombomodulin. Bourin, M.C., Ohlin, A.K., Lane, D.A., Stenflo, J., Lindahl, U. J. Biol. Chem. (1988) [Pubmed]
  27. Thrombin induces nitric-oxide synthase via Galpha12/13-coupled protein kinase C-dependent I-kappaBalpha phosphorylation and JNK-mediated I-kappaBalpha degradation. Kang, K.W., Choi, S.Y., Cho, M.K., Lee, C.H., Kim, S.G. J. Biol. Chem. (2003) [Pubmed]
  28. Anticoagulant and anti-inflammatory effects after peritoneal lavage with antithrombin in experimental polymicrobial peritonitis. VAN Veen, S.Q., Cheung, C.W., Meijers, J.C., VAN Gulik, T.M., Boermeester, M.A. J. Thromb. Haemost. (2006) [Pubmed]
  29. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. Aihara, K., Azuma, H., Akaike, M., Ikeda, Y., Yamashita, M., Sudo, T., Hayashi, H., Yamada, Y., Endoh, F., Fujimura, M., Yoshida, T., Yamaguchi, H., Hashizume, S., Kato, M., Yoshimura, K., Yamamoto, Y., Kato, S., Matsumoto, T. J. Biol. Chem. (2004) [Pubmed]
  30. Increased thrombin inhibition in experimental autoimmune encephalomyelitis. Beilin, O., Karussis, D.M., Korczyn, A.D., Gurwitz, D., Aronovich, R., Hantai, D., Grigoriadis, N., Mizrachi-Kol, R., Chapman, J. J. Neurosci. Res. (2005) [Pubmed]
  31. Membrane chromatography for rapid purification of recombinant antithrombin III and monoclonal antibodies from cell culture supernatant. Lütkemeyer, D., Bretschneider, M., Büntemeyer, H., Lehmann, J. J. Chromatogr. (1993) [Pubmed]
  32. Enzymatic modification of heparan sulfate on a biochip promotes its interaction with antithrombin III. Hernaiz, M., Liu, J., Rosenberg, R.D., Linhardt, R.J. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
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