Disease relevance of PROC

• However, although the fetus carried only the paternal PROS and PROC gene lesions, the child developed renal thrombosis in utero [1].
• A novel homozygous missense mutation in the protein C (PROC) gene causing recurrent venous thrombosis [2].
• The combination of the PROC mutation with a PROS deficiency in two family members triggered venous thromboembolism at age 31 and 6 years, respectively [3].
• TNF, PC, and FPS levels were normal during episodes of cyclosporine toxicity and viral infection.(ABSTRACT TRUNCATED AT 400 WORDS)[4]
• The effects of Factor Va or its light chain on protein C activation were also shown on a mouse hemangioma cell line but not on human fibroblasts nor on a human amelanotic melanoma cell line [5].

Psychiatry related information on PROC

• Measurements of protein C, protein S, and AT III levels were obtained prior to conditioning therapy and weekly thereafter for 2-3 weeks [6].
• Alexia without agraphia following cerebral venous thrombosis associated with protein C and protein S deficiency [7].
• RESULTS: After 1 month of treatment, protein C activity increased by 9.6% and 11.4% of the initial value (p < 0.05), fibrinogen level decreased by 7.8% and 6.1% of the initial value (p < 0.05) and PAI-1 decreased by 19.4% and 14.3% of the initial value (p < 0.05) in the CEE therapy group and the CEE/MPA therapy group, respectively [8].
• Previous measurements of label accessibility to externally added ascorbate had been considered to suggest an external-internal transition of protein-bound labels, coupled with ion translocation [Tonomura, Y. & Morales, M.F. (1974) Proc. Natl. Acad. Sci. USA 71, 3687-3691] [9].
• Cardiac myosin binding protein C gene is specifically expressed in heart during murine and human development [10].

High impact information on PROC

• Plasma levels, protein C antigen, protein S antigen, and antithrombin antigen were lower than those in the controls [11].
• We studied the expression of thrombomodulin and the endothelial protein C receptor in the dermal microvasculature of children with severe meningococcemia and purpuric or petechial lesions [11].
• BACKGROUND: Impairment of the protein C anticoagulation pathway is critical to the thrombosis associated with sepsis and to the development of purpura fulminans in meningococcemia [11].
• Dysfunction of endothelial protein C activation in severe meningococcal sepsis [11].
• CONCLUSIONS: In severe meningococcal sepsis, protein C activation is impaired, a finding consistent with down-regulation of the endothelial thrombomodulin-endothelial protein C receptor pathway [11].

Chemical compound and disease context of PROC

• Protein C inhibitor and other components of the protein C pathway in patients with acute deep vein thrombosis during heparin treatment [12].
• A functionally defective protein C (PC)-Mie, detected the plasma of a patient with hereditary thrombophilia, has Lys substituted for gamma-carboxyglutamic acid (Gla)26 residue [13].
• Coumarin necrosis, neonatal purpura fulminans, and protein C deficiency [14].
• Whether the low protein C, protein S, or antithrombin levels predispose patients with acute leukemia to thrombosis in the absence of DIC is not known [15].
• Patients were screened for hereditary causes of thrombophilia including Protein C, Protein S, antithrombin III, Factor V Leiden and homocysteine [16].

Biological context of PROC

• Molecular genetic analysis of the PROC and PROS gene segregating in the family then yielded one PROC gene lesion in the father and two PROS gene lesions, one in each parent [1].
• We have identified one frameshift (3363 ins C) and two missense mutations (R178Q and T298M) in 7 French Canadian families with type I PROC deficiency [17].
• The frequency of the CG allele associated with lower PC concentrations was slightly but not significantly lower in 82 heterozygotes for detrimental PROC gene mutations than in 36 patients with no identified detrimental mutations [18].
• Our data suggest that these patients carry a common haplotype at the PROC locus [17].
• In order to demonstrate a possible founder effect for the 3363 ins C mutation, we have constructed a high-resolution genetic map to locate several highly polymorphic markers close to PROC locus [17].

Anatomical context of PROC

• Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective [19].
• Protein C functions as an anticoagulant when converted to the active serine protease form on the endothelial cell surface [20].
• Therefore, protein C activation has been believed to occur only in microcirculation [20].
• Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor [20].
• Coagulation factor Va binds to human umbilical vein endothelial cells and accelerates protein C activation [5].

Associations of PROC with chemical compounds

• Genotypic analysis of the second child showed a PROC mutation, but neither PROS mutation consistent with its possession of normal protein S levels and a low/borderline protein C level [1].
• The sequencing of all exons and splice junctions of the PROC gene led to the identification of a new, unpublished G-->A transition at nt 8490, leading to an exchange of alanine 259 by threonine [3].
• In this study we have investigated the effects of Factor Va and its light chain on the activation of protein C in the presence of cultured endothelial cells [5].
• Activation rates of the protein C derivative lacking the gamma-carboxyglutamic acid domain, which is required for binding to EPCR, are not altered by the anti-EPCR antibodies [21].
• Protein C, an anticoagulant zymogen, has Asp residues in positions P3 and P'3 [22].

Physical interactions of PROC

• Thrombomodulin changes the molecular surface of interaction and the rate of complex formation between thrombin and protein C [23].
• EPCR binds to both protein C and activated protein C (APC) with high affinity [24].
• The normal level of PC inhibitor and APC:PCI complex found in this study provided no evidence of increased consumption of protein C in thalassemia patients [25].
• The endothelial PC receptor binds the Gla domain of PC and stimulates the activation [26].
• Eight of these were novel, including a gross gene deletion, three missense mutations, two micro-deletions, a splicing mutation and a single base-pair substitution in the HNF-3 binding site in the PROC gene promoter [27].

Enzymatic interactions of PROC

• Protein C activation is catalyzed by a complex of thrombin (T) with thrombomodulin (TM) [28].
• Gene structure of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for thrombin-catalyzed activation of protein C [29].

Regulatory relationships of PROC

• Although protein C can be activated directly by the thrombin-TM complex, the conversion is known as a relatively low-affinity reaction [20].
• In vitro cultured, arterial endothelial cells were also found to express abundant EPCR and were capable of promoting significant levels of protein C activation [20].
• Protein S is a cofactor for activated protein C neutralization of an inhibitor of plasminogen activation released from platelets [30].
• Platelet factor 4 binds to glycanated forms of thrombomodulin and to protein C. A potential mechanism for enhancing generation of activated protein C [31].
• Provided that thrombomodulin EGF-like domain 3 was present, TAFI competitively inhibited protein C activation catalyzed by the thrombin-thrombomodulin complex [32].

Other interactions of PROC

• Here we present the 2.3 A crystal structure of human alpha-thrombin bound to the smallest thrombomodulin fragment required for full protein-C co-factor activity, TME456 [33].
• By these mechanisms, EPCR appears to enable significant levels of protein C activation in large vessels [20].
• We studied the relation between heritable thrombophilic defects and fetal loss in a cohort of women with factor V Leiden or deficiency of antithrombin, protein C, or protein S. METHODS: We studied 1384 women enrolled in the European Prospective Cohort on Thrombophilia (EPCOT) [34].
• Addition of PCI to normal plasma and protein C-deficient plasma resulted in a minor prolongation of the clotting time [35].
• When the TFPI concentration was reduced to 1.25 nM, thrombin generation is still curtailed in the presence of normal factor V. In contrast, under similar conditions using factor VLEIDEN, the protein C pathway totally failed to down-regulate thrombin generation [36].

Analytical, diagnostic and therapeutic context of PROC

• Using a highly sensitive RT-PCR assay, we show here that aberrant splicing is a frequent occurrence during expression of the protein C (PROC) and protein S (PROS) genes [37].
• PROC and PROS deficiency were documented by functional and immunologic tests [3].
• Plasma samples (n = 454) were collected three times/week from all patients (n = 25) undergoing renal transplantation during a 9-month consecutive period, and assayed by ELISA and functional assays for TNF, PC, and free PS (FPS) [4].
• Using specific radioimmunoassays, 8 day cultures of Hep G2 cells were shown to contain in their supernatants 16, 74, and 828 ng/mL and in their cell lysates, 8, 55, and 48 ng/2 X 10(8) cells of factor VII, protein C, and protein S, respectively [38].
• No significant differences exist between survivors and nonsurvivors with respect to baseline PC levels, F1 + 2 levels, and APACHE II (acute physiology and chronic health evaluation) scores [39].

References