Disease relevance of Proc

• P-selectin facilitates human carcinoma metastasis in immunodeficient mice by mediating early interactions of platelets with bloodborne tumor cells via their cell surface mucins, and this process can be blocked by heparin [Borsig, L., Wong, R., Feramisco, J., Nadeau, D. R., Varki, N. M. & Varki, A. (2001) Proc. Natl. Acad. Sci. USA 98, 3352-3357] [1].
• While retroviruses can deliver siRNA expression cassettes for stable expression (Barton and Medzhitov: Proc Natl Acad Sci USA 99:14943-14945, 2002; Paddison et al.: Proc Natl Acad Sci USA 99:1443-1448, 2002; Rubinson et al.: Nat Genet 33:401-406, 2003), an efficient method for direct transfer of siRNA to stem cells is still lacking [2].
• Microscopic examination of tissues and blood vessels of E17.5 PC-/- mice revealed their normal development, but scattered microvascular thrombosis in the brain combined with focal necrosis in the liver was observed [3].
• These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis [4].
• Mice with single-allele targeted disruption of the protein C gene (PC+/-) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally [4].

Psychiatry related information on Proc

• We recently reported [Proc. Natl. Acad. Sci. USA 95 (1998) 3239] that in patients with severe depression there is a decrease in the CSF levels of 3alpha,5alpha-TH PROG, which is normalized by treatment with drugs (i.e. fluoxetine) that improve psychopathology [5].
• Cardiac myosin binding protein C gene is specifically expressed in heart during murine and human development [6].

High impact information on Proc

• The thrombomodulin-protein C system is essential for the maintenance of pregnancy [7].
• Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities [8].
• In contrast to PC-/- mice, mice with only partial PC deficiency survived beyond birth and also developed thrombosis and inflammation [8].
• Anticoagulant protein C (PC) is important not only for maintenance of normal hemostasis, but also for regulating the host immune response during inflammation [8].
• Our findings additionally provide the first evidence that maternal PC is vital for sustaining pregnancy beyond 7.5 days postcoitum, likely by regulating the balance of coagulation and inflammation during trophoblast invasion [8].

Chemical compound and disease context of Proc

• Protein C (PC) is a vitamin K-dependent serine protease, a deficiency of which results in thrombus [9].
• Mouse hepatitis virus binds to the N-terminal domain of its receptor, MHVR, a murine biliary glycoprotein with four immunoglobulin-like domains (G.S. Dveksler, M. N. Pensiero, C. W. Dieffenbach, C. B. Cardellichio, A.A. Basile, P.E. Elia, and K. V. Holmes, Proc. Natl. Acad. Sci. USA 90:1716-1720, 1993) [10].
• These 5'-terminal sequences are the same as those proposed for rat hepatoma U1 and U2 RNAs (Ro-Choi et al., Fed. Proc. 33, 1548, 1974) but with triphosphate rather than diphosphate links [11].
• The PYS-2 cultures were shown by immunofluorescence to react with antibodies against the heparan sulfate-containing proteoglycan isolated from the mouse EHS sarcoma (Hassell, J. R., P. G. Robey, H. J. Barrach, J. Wilczek, S. I. Rennard, and G. R. Martin. 1980. Proc. Natl. Acad. Sci. U. S. A. 77:4494-4498) [12].
• The mechanism of action of hepsulfam is not known and it has recently been entered into Phase I clinical trials by the National Cancer Institute. Waud et al. have recently shown that hepsulfam has good antitumor activity against mouse L1210 leukemia in vivo (Waud et al., Proc. Am. Assoc. Cancer Res., 29:333, 1988) [13].

Biological context of Proc

• Recently, our laboratory showed that platelets, like leukocytes, roll on activated endothelium expressing P-selectin, thus suggesting a role for P-selectin in hemostasis (Frenette et at, Proc Natl Acad Sci USA 92:7450, 1995) [14].
• It has been proposed on the basis of amino acid sequence homology that the leukocyte common antigen CD45 represents a family of catalytically active, receptor-linked protein tyrosine phosphatases [Charbonneau, H., Tonks, N. K., Walsh, K. A., & Fischer, E. H. (1988) Proc. Natl. Acad. Sci. U.S.A. 85, 7182-7186] [15].
• The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin [4].
• No signs of severe disseminated intravascular coagulation (DIC) were observed in wild-type or PC(+/-) mice, as indicated by an increase in fibrinogen levels and the invariability of platelet counts after cecal ligation and puncture [16].
• Consumption of coagulation factors was similar in both genotypes and a decrease in the PC mRNA and protein levels was more prominent in PC(+/-) mice [16].

Anatomical context of Proc

• The deduced protein sequence differs from that previously reported for a T-cell form of the molecule [Saga, Y., Tung, J.-S., Shen, F.-W. & Boyse, E. A. (1986) Proc. Natl. Acad. Sci. USA 83, 6940-6944] by the insertion of 139 amino acid residues in the amino-terminal region of the molecule [17].
• These findings show a new function for the thrombomodulin-protein C system in controlling the growth and survival of trophoblast cells in the placenta [7].
• Thrombin-catalyzed activation of Protein C is accelerated by a human endothelial cell surface cofactor [18].
• Renal and organ muscle damage was enhanced in PC(+/-) mice, as shown by increases in plasma blood urea nitrogen, creatinine, and creatinine kinase [16].
• Finally, we documented calcium-dependent activation of protein C by a thrombin:TM complex with thrombin added to the astrocytes [19].

Associations of Proc with chemical compounds

• IMAC could replace the immunoaffinity technology for the large-scale separation of protein C from blood plasma Cohn Fraction IV-1 [20].
• Following protein adsorption to the column, prothrombin was washed out using a sodium phosphate buffer containing 2 mM imidazole and protein C was recovered with 15 mM imidazole in the buffer [20].
• Mouse PC also had several structural features common in other PCs; locations of 23 Cys residues, location of putative beta-hydroxy Asp71, possible carbohydrate attachment sites involving Asp residues at amino acid positions 249, 314, and 330, and location of active sites such as His212, Asp258, and Ser361 [9].
• We conclude that influenza infection generates thrombin, increased by reduced levels of protein C and decreased by heparin [21].
• Thrombomodulin mutant mice with a strongly reduced capacity to generate activated protein C have an unaltered pulmonary immune response to respiratory pathogens and lipopolysaccharide [22].

Physical interactions of Proc

• All three antibodies bound to the light chain of protein C on immunoblots and also bound to the homologous proteins factor X and prothrombin in solid-phase radioimmunoassays [23].
• Hypercontractile properties of cardiac muscle fibers in a knock-in mouse model of cardiac myosin-binding protein-C [24].

Regulatory relationships of Proc

• A thrombomodulin mutation that impairs activated protein C generation results in uncontrolled lung inflammation during murine tuberculosis [25].

Other interactions of Proc

• FVII(-/-)/PC(-/-) embryos, although present at their expected Mendelian frequency, displayed a phenotype that had not been observed in either the FVII or PC singly deficient embryos [26].
• Collectively, these results support the hypothesis that PCI may contribute to proteolysis equilibrium within the testis by acting in tandem with urokinase in Leydig cells and with PC and/or urokinase in spermatogenic cells [27].
• Effects on coagulation and fibrinolysis induced by influenza in mice with a reduced capacity to generate activated protein C and a deficiency in plasminogen activator inhibitor type 1 [21].
• In previous studies, mice whose genes for the estrogen receptor-alpha (alpha-ERKO) and estrogen receptor-beta (beta-ERKO) as well as OTKO were knocked out failed to habituate to a repeatedly presented conspecific and to dishabituate when the familiar mouse is replaced by a novel animal (Choleris et al. 2003, Proc Natl Acad Sci USA 100, 6192-6197) [28].
• 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 [29].

Analytical, diagnostic and therapeutic context of Proc

• These low PC-expressing transgenic mouse lines provide novel animal models that can be used to elucidate the importance of PC in maintenance of the organism and in disease [8].
• A protein C deficiency exacerbates inflammatory and hypotensive responses in mice during polymicrobial sepsis in a cecal ligation and puncture model [16].
• The occurrence of testicular target proteases for PCI, i.e. PC and urokinase- and tissue-type PA, was further tracked using RT-PCR, plasminogen zymography, and/or immunohistochemistry [27].
• A novel ELISA for mouse activated protein C in plasma [30].
• Northern blot hybridization analysis identified a single species of mouse PC mRNA (2.0 kb in length) in mouse liver [9].

References