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Gene Review

Proc  -  protein C

Rattus norvegicus

Synonyms: Anticoagulant protein C, Autoprothrombin IIA, Blood coagulation factor XIV, Vitamin K-dependent protein C
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Disease relevance of Proc

  • Rasheed rat sarcoma virus, derived by in vitro cocultivation of two rat cell lines (Rasheed et al., Proc. Natl. Acad. Sci. U.S.A. 75:2972-2976, 1978), has been reported to code for a protein of 29,000 Mr, immunologically related to the 21,000 Mr src gene product of Harvey and Kirsten sarcoma viruses [1].
  • Protein C activation has been shown to be critical to the host defense against septic shock [2].
  • Neither enzyme-linked immunosorbent assays, nor protein C activation assays showed decreased levels in TM antigen expression or activity at different time points during the sepsis [3].
  • First, NGF rapidly stimulates tyrosine phosphorylation of several unidentified proteins in the NGF-responsive pheochromocytoma cell line PC12 [Maher, P. (1988) Proc. Natl. Acad. Sci. USA 85, 6788-6791] [4].
  • Asbestos and the phorbol ester tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), increase c-fos and c-jun mRNA levels and AP-1 DNA binding activity in rat pleural mesothelial (RPM) cells, a target cell of asbestos-induced mesotheliomas (N. H. Heintz et al., Proc. Natl. Acad. Sci. USA, 90: 3299-3303, 1993) [5].

High impact information on Proc

  • In contrast to results with total rat liver mRNA, injection of mRNA derived from the Na+/bile acid cotransporter cDNA (Hagenbuch, B., B. Stieger, M. Foguet, H. Lübbert, and P. J. Meier. 1991. Proc. Natl. Acad. Sci. USA. In press.) had no effect on BSP uptake into oocytes [6].
  • We previously demonstrated an alternate pathway for the biosynthesis of 5-aminolevulinic acid (ALA) in bovine liver mitochondria and of tetrapyrroles in suspensions of rat hepatocytes (1980. J. Biol. Chem. 255: 3742; 1981. Proc. Natl. Acad. Sci. USA. 78: 5335) [7].
  • Immature secretory granules (ISGs) in endocrine and neuroendocrine cells have been shown by morphological techniques to be partially clathrin coated (Orci, L., M. Ravazzola, M. Amherdt, D. Lonvard, A. Perrelet. 1985a. Proc. Natl. Acad. Sci. USA. 82:5385-5389; Tooze, J., and S. A. Tooze. 1986. J. Cell Biol. 103:839-850) [8].
  • The dynamic intra-nuclear localization of MRP RNA, the RNA component of the ribonucleoprotein enzyme RNase MRP, was examined in living cells by the method of fluorescent RNA cytochemistry (Wang, J., L.-G. Cao, Y.-L. Wang, and T. Pederson. 1991. Proc. Natl. Acad. Sci. USA. 88:7391-7395) [9].
  • Functionally the cytosolic p62 complex must bind to TGN38/41 for the budding of exocytic transport vesicles from the TGN as assayed in a cell-free system (Salamero, J., E. S. Sztul, and K. E. Howell. 1990. Proc. Natl. Acad. Sci. USA. 87:7717-7721) [10].

Chemical compound and disease context of Proc

  • The NH2-terminal gamma-carboxylated fragments of prothrombin which induce prothrombin synthesis (Graves, C. B., Munns, T. W., Carlisle, T. L., Grant, G. A., and Strauss, A. W. (1981) Proc. Natl. Acad. Sci. U. S. A. 78, 4772-4776) also induce single chain X synthesis by hepatoma cells [11].
  • A carboxyl fragment of the membrane form of guanylate cyclase from rat brain, which contains a region homologous to soluble guanylate and adenylate cyclases, was expressed in Escherichia coli with a double plasmid system that encodes T7 RNA polymerase (Tabor, S., and Richardson, C.C. (1985) Proc. Natl. Acad. Sci. U. S. A. 82, 1074-1078) [12].
  • Transfection of C6 glioma cells with connexin43 (Cx43) cDNA under a constitutive promoter resulted in expression of Cx43 protein, an increase in functional gap junctions, and reduced growth under in vitro and in vivo conditions (D. Zhu et al., Proc. Natl. Acad. Sci. USA, 88: 1883-1887, 1991) [13].
  • We have observed that an early event accompanying doxorubicin cardiomyopathy is a selective decrease in levels of muscle gene transcripts in cardiac tissue (Ito et al., Proc. Natl. Acad. Sci. USA 87: 4275-4279) [14].
  • A band of gp330, which was identified as a pathogenic antigen of Heymann nephritis by Kerjaschki D and Farquhar MG (Proc Natl Acad Sci USA 79:5557, 1982) was detected as another band by Coomassie blue staining and immunoblotting [15].

Biological context of Proc

  • Rat primary MCs were stably transfected (using strontium phosphate DNA coprecipitation) with a plasmid containing the gene for rat thrombomodulin (TM), a transmembrane glycoprotein that functions as an essential cofactor for the physiological activation of the anticoagulant protein C by the enzyme thrombin [16].
  • BACKGROUND: The thrombomodulin-dependent protein C anticoagulant pathway plays a major physiologic role in the down-regulation of the coagulation process [3].
  • By transfection of the thrombomodulin gene in IVCs, the generation capacity of activated protein C in venous endothelium increased three-fold compared with veins treated with vector alone (P<0.01) [17].
  • The amino acid sequence deduced from the shorter transcript is identical to a precursor form of secretin recently isolated from porcine duodenum [Gafvelin, G., Jornvall, H. & Mutt, V. (1990) Proc. Natl. Acad. Sci. USA 87, 6781-6785] [18].
  • [Fujii-Kuriyama, Y., Mizukami, Y., Kamajiri, K., Sogawa, K. & Muramatsu, M. (1982) Proc. Natl. Acad. Sci. USA 79, 2793-2797] encode cytochrome P-450b whereas pcP-450pb2, a third cDNA whose nucleotide sequence differed slightly from that of the other two (six amino acid substitutions), encodes cytochrome P-450e [19].

Anatomical context of Proc

  • Moreover, the recombinant TM expressed on the reconstituted parietal mesothelium retained its ability to activate protein C in a thrombin-dependent manner [16].
  • Activated protein C reduces stress-induced gastric mucosal injury in rats by inhibiting the endothelial cell injury [20].
  • At 3 min, 125I-insulin has been shown to be exclusively localized to the hepatocyte plasmalemma (Bergeron et al., 1977, Proc. Natl. Acad. Sci. U. S. A., 74:5051--5055) [21].
  • About half of the microtubules have their plus ends oriented distal to the cell body, and the other half have their minus ends distal; in contrast, microtubules in the axon are of uniform polarity orientation, all having their plus ends distal (Baas, P.W., J.S. Deitch, M. M. Black, and G. A. Banker. 1988. Proc. Natl. Acad. Sci. USA. 85:8335-8339) [22].
  • In rat liver, this monoclonal antibody, mAb 414, binds to nuclear pore complex proteins, including one of molecular weight 62,000 (Davis, L. I., and G. Blobel. 1987. Proc. Natl. Acad. Sci. USA. 84:7552-7556) [23].

Associations of Proc with chemical compounds

  • 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key regulatory enzyme involved in cholesterol biosynthesis, has recently been reported to be present in rat liver peroxisomes (Keller, G.A., M.C. Barton, D.J. Shapiro, and S.J. Singer, 1985, Proc. Natl. Acad. Sci. USA, 82:770-774) [24].
  • These entities have been interpreted as the "primitive" counterpart of the SR, and suggested to be the organelle target of inositol-1,4,5-triphosphate action (Volpe, P., K. H. Krause, S. Hashimoto, F. Zorzato, T. Pozzan, J. Meldolesi, and D. P. Lew. Proc. Natl. Acad. Sci. USA. 85:1091-1095) [25].
  • The concentration of MgCl2 (2 mM) at which turbidity of nuclear suspensions is maximal and chromatin condensation appears most extensive is the same concentration that reportedly (Gottesfeld et al., 1974, Proc. Natl. Acad. Sci. U. S. A. 71:2193-2197) precipitates "inactive" chromatin [26].
  • A low pH method of liposome-membrane fusion (Schneider et al., 1980, Proc. Natl. Acad. Sci. U. S. A. 77:442) was used to enrich the mitochondrial inner membrane lipid bilayer 30-700% with exogenous phospholipid and cholesterol [27].
  • With a lower detergent-to-cell ratio during lysis, significant Fc epsilon RI remains associated with these membrane domains, consistent with the ability to coimmunoprecipitate tyrosine kinase activity with Fc epsilon RI under similar lysis conditions [Pribluda, V. S., Pribluda, C. & Metzger, H. (1994) Proc. Natl. Acad. Sci. USA 91, 11246-11250] [28].

Other interactions of Proc

  • The endothelial cell protein C receptor (EPCR) facilitates protein C activation by the thrombin-thrombomodulin complex [2].
  • As judged by a thrombin-dependent protein C activation assay, such MC membrane-bound TM was biologically active [16].
  • Microsequence analysis of the protein purified by gel-filtration HPLC and SDS/PAGE showed complete identity within the first 41 N-terminal amino acids with the deduced protein sequence of cysteine-rich intestinal protein [Birkenmeier, E. H. & Gordon, J. I. (1986) Proc. Natl. Acad. Sci. USA 83, 2516-2520] [29].
  • It is also found that the primary structure thus predicted has striking homology to that of gp 110, a bile canaliculus domain-specific membrane glycoprotein (Hong, W., and Doyle, D. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 7962-7966) [30].
  • Guanylin (PNTCEICAYAACTGC) is a peptide recently isolated from the intestine, the actions of which appear to be mimicked by bacterial heat-stable enterotoxins (Currie, M. G., Fok, K. F., Kato, J., Moore, R. J., Hamra, F. K., Duffin, K. L., and Smith, C. E. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 947-951) [31].

Analytical, diagnostic and therapeutic context of Proc

  • Northern blot analysis showed that the rat protein C mRNA was expressed not only in the liver, but also in the kidney [32].
  • To address these issues, we used a fully defined neuronal cell culture system derived from embryonic rat sympathetic ganglia (DiCicco-Bloom, E., and I. B. Black. 1988. Proc. Natl. Acad. Sci. USA. 85:4066-4070) in which precursors enter the mitotic cycle [33].
  • Anti-synapsin I immunoperoxidase staining of tissue sections for electron microscopy produced an uneven labeling of terminals of the neuropile, in agreement with results of a previous study (Bloom, F. E., T. Ueda, E. Battenberg, and P. Greengard, 1979, Proc. Natl. Acad. Sci. USA. 76:5982-5986) [34].
  • In all fibroblast cell lines examined, we also found a Mr 77,000 protein that crossreacts with anti-caldesmon150 antibody by using an immunoprecipitation technique [Owada, M.K., Hakura, A., Iida, K., Yahara, I., Sobue, K. & Kakiuchi, S. (1984) Proc. Natl. Acad. Sci. USA 81, 3133-3137] [35].
  • Colchicine, which has previously been shown to prevent the onset of DNA synthesis (Walker, P. R., and Whitfield, J. F. (1978) Proc. Natl. Acad. Sci. U. S. A. 75, 1394-1398), also prevents the increased protein kinase activity normally observed 16 h after partial hepatectomy [36].


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  2. Endotoxin and thrombin elevate rodent endothelial cell protein C receptor mRNA levels and increase receptor shedding in vivo. Gu, J.M., Katsuura, Y., Ferrell, G.L., Grammas, P., Esmon, C.T. Blood (2000) [Pubmed]
  3. Lack of suppressed renal thrombomodulin expression in a septic rat model with glomerular thrombotic microangiopathy. Laszik, Z., Carson, C.W., Nadasdy, T., Johnson, L.D., Lerner, M.R., Brackett, D.J., Esmon, C.T., Silva, F.G. Lab. Invest. (1994) [Pubmed]
  4. Nerve growth factor rapidly stimulates tyrosine phosphorylation of phospholipase C-gamma 1 by a kinase activity associated with the product of the trk protooncogene. Vetter, M.L., Martin-Zanca, D., Parada, L.F., Bishop, J.M., Kaplan, D.R. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  5. Inhibition of protein kinase C prevents asbestos-induced c-fos and c-jun proto-oncogene expression in mesothelial cells. Fung, H., Quinlan, T.R., Janssen, Y.M., Timblin, C.R., Marsh, J.P., Heintz, N.H., Taatjes, D.J., Vacek, P., Jaken, S., Mossman, B.T. Cancer Res. (1997) [Pubmed]
  6. Expression of the hepatocellular chloride-dependent sulfobromophthalein uptake system in Xenopus laevis oocytes. Jacquemin, E., Hagenbuch, B., Stieger, B., Wolkoff, A.W., Meier, P.J. J. Clin. Invest. (1991) [Pubmed]
  7. Biosynthesis of 5-aminolevulinic acid and heme from 4,5-dioxovalerate in the rat. Morton, K.A., Kushner, J.P., Straka, J.G., Burnham, B.F. J. Clin. Invest. (1983) [Pubmed]
  8. The AP-1 adaptor complex binds to immature secretory granules from PC12 cells, and is regulated by ADP-ribosylation factor. Dittie, A.S., Hajibagheri, N., Tooze, S.A. J. Cell Biol. (1996) [Pubmed]
  9. Dynamic localization of RNase MRP RNA in the nucleolus observed by fluorescent RNA cytochemistry in living cells. Jacobson, M.R., Cao, L.G., Wang, Y.L., Pederson, T. J. Cell Biol. (1995) [Pubmed]
  10. A cytosolic complex of p62 and rab6 associates with TGN38/41 and is involved in budding of exocytic vesicles from the trans-Golgi network. Jones, S.M., Crosby, J.R., Salamero, J., Howell, K.E. J. Cell Biol. (1993) [Pubmed]
  11. Rat factor X is synthesized as a single chain precursor inducible by prothrombin fragments. Graves, C.B., Munns, T.W., Willingham, A.K., Strauss, A.W. J. Biol. Chem. (1982) [Pubmed]
  12. The carboxyl region contains the catalytic domain of the membrane form of guanylate cyclase. Thorpe, D.S., Morkin, E. J. Biol. Chem. (1990) [Pubmed]
  13. Analysis of connexin43 expression under the control of a metallothionein promoter. Bechberger, J.F., Khoo, N.S., Naus, C.C. Cell Growth Differ. (1996) [Pubmed]
  14. Evaluation of mRNA levels by the polymerase chain reaction in small cardiac tissue samples. Ito, H., Miller, S.C., Akimoto, H., Torti, S.V., Taylor, A., Billingham, M.E., Torti, F.M. J. Mol. Cell. Cardiol. (1991) [Pubmed]
  15. Passive Heymann nephritis with acute and severe proteinuria induced by heterologous antibody against renal tubular brush border glycoprotein gp108. Natori, Y., Hayakawa, I., Shibata, S. Lab. Invest. (1986) [Pubmed]
  16. Enhancement of the functional repertoire of the rat parietal peritoneal mesothelium in vivo: directed expression of the anticoagulant and antiinflammatory molecule thrombomodulin. Jackman, R.W., Stapleton, T.D., Masse, E.M., Harvey, V.S., Meyers, M.S., Shockley, T.R., Nagy, J.A. Hum. Gene Ther. (1998) [Pubmed]
  17. Non-viral in vivo thrombomodulin gene transfer prevents early loss of thromboresistance of grafted veins. Tabuchi, N., Shichiri, M., Shibamiya, A., Koyama, T., Nakazawa, F., Chung, J., Hirosawa, S., Sunamori, M. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. (2004) [Pubmed]
  18. The secretin gene: evolutionary history, alternative splicing, and developmental regulation. Kopin, A.S., Wheeler, M.B., Nishitani, J., McBride, E.W., Chang, T.M., Chey, W.Y., Leiter, A.B. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  19. Identification and localization of amino acid substitutions between two phenobarbital-inducible rat hepatic microsomal cytochromes P-450 by micro sequence analyses. Yuan, P.M., Ryan, D.E., Levin, W., Shively, J.E. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  20. Activated protein C reduces stress-induced gastric mucosal injury in rats by inhibiting the endothelial cell injury. Isobe, H., Okajima, K., Harada, N., Liu, W., Okabe, H. J. Thromb. Haemost. (2004) [Pubmed]
  21. Binding and uptake of 125I-insulin into rat liver hepatocytes and endothelium. An in vivo radioautographic study. Bergeron, J.J., Sikstrom, R., Hand, A.R., Posner, B.I. J. Cell Biol. (1979) [Pubmed]
  22. Changes in microtubule polarity orientation during the development of hippocampal neurons in culture. Baas, P.W., Black, M.M., Banker, G.A. J. Cell Biol. (1989) [Pubmed]
  23. Yeast nuclear envelope proteins cross react with an antibody against mammalian pore complex proteins. Aris, J.P., Blobel, G. J. Cell Biol. (1989) [Pubmed]
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  25. Immunocytochemistry of calciosomes in liver and pancreas. Hashimoto, S., Bruno, B., Lew, D.P., Pozzan, T., Volpe, P., Meldolesi, J. J. Cell Biol. (1988) [Pubmed]
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  27. Relationship between the density distribution of intramembrane particles and electron transfer in the mitochondrial inner membrane as revealed by cholesterol incorporation. Schneider, H., Höchli, M., Hackenbrock, C.R. J. Cell Biol. (1982) [Pubmed]
  28. Fc epsilon RI-mediated recruitment of p53/56lyn to detergent-resistant membrane domains accompanies cellular signaling. Field, K.A., Holowka, D., Baird, B. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  29. Cysteine-rich intestinal protein binds zinc during transmucosal zinc transport. Hempe, J.M., Cousins, R.J. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  30. Primary structure of rat liver dipeptidyl peptidase IV deduced from its cDNA and identification of the NH2-terminal signal sequence as the membrane-anchoring domain. Ogata, S., Misumi, Y., Ikehara, Y. J. Biol. Chem. (1989) [Pubmed]
  31. Cloning and expression of guanylin. Its existence in various mammalian tissues. Schulz, S., Chrisman, T.D., Garbers, D.L. J. Biol. Chem. (1992) [Pubmed]
  32. The cDNA cloning and mRNA expression of rat protein C. Okafuji, T., Maekawa, K., Nawa, K., Marumoto, Y. Biochim. Biophys. Acta (1992) [Pubmed]
  33. Neuroblast mitosis in dissociated culture: regulation and relationship to differentiation. DiCicco-Bloom, E., Townes-Anderson, E., Black, I.B. J. Cell Biol. (1990) [Pubmed]
  34. Synapsin I (Protein I), a nerve terminal-specific phosphoprotein. II. Its specific association with synaptic vesicles demonstrated by immunocytochemistry in agarose-embedded synaptosomes. De Camilli, P., Harris, S.M., Huttner, W.B., Greengard, P. J. Cell Biol. (1983) [Pubmed]
  35. Purification and characterization of caldesmon77: a calmodulin-binding protein that interacts with actin filaments from bovine adrenal medulla. Sobue, K., Tanaka, T., Kanda, K., Ashino, N., Kakiuchi, S. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  36. Modulation of nuclear protein kinase activity and phosphorylation of histone H1 subspecies during the prereplicative phase of rat liver regeneration. Laks, M.S., Harrison, J.J., Schwoch, G., Jungmann, R.A. J. Biol. Chem. (1981) [Pubmed]
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