The structure and evolution of a 461 amino acid human protein C precursor and its messenger RNA, based upon the DNA sequence of cloned human liver cDNAs

Beckmann, Robert J.; Schmidt, Robert J.; Santerre, Robert F.; Plutzky, Jorge; Crabtree, Gerald R.; Long, George L.

doi:10.1093/nar/13.14.5233

Cited by 150 publications

(73 citation statements)

References 41 publications

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“…[1][2][3] Whereas synthesis predominantly occurs in the liver, PC has also been identified in the epididymus, kidney, lung, brain, and male reproductive tissue. 4 Cotranslational and posttranslational modifications of PC include ␤-hydroxylation, ␥-carboxylation, and glycosylation; the ␥-carboxylation is required for efficient secretion and for the anticoagulant activity of PC.…”

Section: Pc Pathway In Hemostasismentioning

confidence: 99%

The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications

Danese

Vetrano

Zhang

et al. 2010

Blood

132

120

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Inflammation and coagulation are closely linked interdependent processes. Under physiologic conditions, the tissue microcirculation functions in anticoagulant and anti-inflammatory fashions. However, when inflammation occurs, coagulation is also set in motion and actively participates in enhancing inflammation. Recently, novel and unexpected roles of hemostasis in the humoral and cellular components of innate immunity have been described. In particular, the protein C system, besides its well-recognized role in anticoagulation, plays a crucial role in inflammation. Indeed, the protein C system is now emerging as a novel participant in the pathogenesis of acute and chronic inflammatory diseases, such as sepsis, asthma, inflammatory bowel disease, atherosclerosis, and lung and heart inflammation, and may emerge as unexpected therapeutic targets for intervention. (Blood.

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Section: Pc Pathway In Hemostasismentioning

confidence: 99%

The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications

Danese

Vetrano

Zhang

et al. 2010

Blood

132

120

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“…A full-length cDNA and a genomic copy of protein C have been cloned and sequenced (12)(13)(14)(15), and the gene has been mapped to chromosome 2 (16). Several abnormalities in the DNA have been found to underlie protein C deficiency; these include gross deletions, nonsense mutations, missense mutations, and a frameshift mutation (17)(18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Impaired secretion of the elongated mutant of protein C (protein C-Nagoya). Molecular and cellular basis for hereditary protein C deficiency.

Yamamoto

Tanimoto²,

Emi

et al. 1992

J. Clin. Invest.

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Genetic analysis of a heterozygous protein C-deficient patient revealed a novel deletion of a single guanine residue ("'7G) among four consecutive guanine nucleotides [3Trp(TGG)-31Gly(GGT)j in exon IX, which encodes the carboxyl-terminal region of protein C. This deletion results in a frameshift mutation and substitution of the last 39 amino acids ("1Gly-419Pro) with 81 abnormal amino acid residues, and we have designated this elongated variant as Protein C-Nagoya. A mutagenic primer was designed which replaced the third guanine residue upstream from the deletion with cytosine, thereby creating a new Aval site in an otherwise normal allele. Analysis of the polymerase chain reaction products derived from this. mutagenic primer showed that the abnormal allele has been inherited in this family. To elucidate how this molecular abnormality leads to protein C deficiency, an expression plasmid containing this mutation was transfected into COS 7, BHK, and P-2 cells, and the secretory process of the expressed Protein C-Nagoya was analyzed. ELISA and immunoprecipitation analysis with I35Slmethionine labeling indicated that the mutant protein C, which was larger in size than normal, was mostly retained within the cells, and only a small portion of it was secreted into the medium. These results suggest that most of Protein C-Nagoya undergoes degradation within the producing cells, and this frameshift mutation apparently leads to protein C deficiency by impairment of secretion of the elongated protein C into plasma. (J. Clin. Invest. 1992.90:2439-2446

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“…A deficiency of protein S, the cofactor for protein C-mediated inactivation of factor Va, has been reported as also causing increased thrombosis (13). Partial cDNAs for protein C were characterized by Foster and Davie (14), and a full length cDNA giving the complete amino acid sequence ofthe human protein has been isolated in our laboratory (36). We (15) using a protein C cDNA (36) corresponding to amino acids 225-419 plus the 3' nontranslated region.…”

mentioning

confidence: 99%

Evolution and organization of the human protein C gene.

Plutzky¹,

Hoskins²,

Long³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

177

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We have isolated overlapping phage genomic clones covering an area of 21 kilobases that encodes the human protein C gene. The gene is at least 11.2 kilobases long and is made up of nine exons and eight introns. Two regions homologous to epidermal growth factor and transforming growth factor are encoded by amino acids 46-91 and 92-136 and are precisely delimited by introns, as is a similar sequence in the genes for coagulation factor IX and tissue plasminogen activator. When homologous amino acids of factor IX and protein C are aligned, the positions of all eight introns correspond precisely, suggesting that these genes are the product of a relatively recent gene duplication. Nevertheless, the two genes are sufficiently distantly related that no nucleic acid homology remains in the *ntronic regions and that the size of the introns varies dramatically between the two genes. The similarity of the genes for factor IX and protein C suggests that they may be the most closely related members of the serine protease gene family involved in coagulation and fibrinolysis.Protein C is a two-chain vitamin K-dependent serine protease that plays. a fundamental role in hemostasis by preventing coagulation and promoting fibrinolysis (1). The anticoagulant effects of protein C are achieved through cleavage of factors Va and Villa of the intrinsic pathway (2), while clot lysis appears to result from interaction of protein C with the inhibitor of plasminogen activator (3). First isolated from bovine plasma in 1976 by Stenflo (4), the human protein (5) has since been shown to be a 62-kDa dimer with a heavy chain that contains the active serine site and a light chain that contains, at its amino terminus, y--carboxylglutamic acid residues, which are highly conserved among the vitamin K-dependent factors (6). The protein circulates as a zymogen (7), is activated by thrombin coupled with an endothelial cofactor, thrombomodulin (8), and is inactivated by a specific plasma protease inhibitor (9). Heterozygous deficiency of protein C was first identified by Griffin et al. (10) and has been shown by several workers to be an autosomally dominant disorder manifested by a markedly increased tendency to clot (11). Homozygous protein C-deficient patients, with no detectable antigenic levels of protein C, suffer from massive venous thrombosis as neonates (12). A deficiency of protein S, the cofactor for protein C-mediated inactivation of factor Va, has been reported as also causing increased thrombosis (13 kilobase pairs (kbp), were mapped using the restriction enzymes BamHI, EcoRI, HindIII, Pst I, and Sma I. DNA Sequencing. Genomic subfragments (see Fig. 1) from isolated X phage were ligated into the appropriate restriction sites of plasmid pBR322, and the resulting chimeric plasmids were grown in Escherichia coli strain RR1 using standard procedures. Plasmid DNA was purified by CsCl banding as described elsewhere (36).The strategy utilized to locate the desired regions for sequencing (intron-exon junctions and all exonic segments) was...

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The structure and evolution of a 461 amino acid human protein C precursor and its messenger RNA, based upon the DNA sequence of cloned human liver cDNAs

Cited by 150 publications

References 41 publications

The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications

The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications

Impaired secretion of the elongated mutant of protein C (protein C-Nagoya). Molecular and cellular basis for hereditary protein C deficiency.

Evolution and organization of the human protein C gene.

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