Disease relevance of PROS1

• In the course of investigating the molecular basis of protein S deficiency in 31 index cases with thrombophilia, we identified seven kindred where the underlying defect was a novel A to G transition 9 bp upstream of exon 12 in intron K of the PROS1 gene [1].
• Our data suggest that the determination of protein S levels will be useful in the evaluation of patients with recurrent thrombosis [2].
• Using this test, we have now identified six unrelated persons with severe recurrent venous thrombosis who were deficient in protein S, with levels between 15 and 37 per cent while they were not receiving warfarin therapy [2].
• Recurrent venous thromboembolism in patients with a partial deficiency of protein S [2].
• When 20 normal plasmas were tested using this clotting assay, apoA-I levels correlated with anticoagulant response to APC/protein S (r = 0.47, P = 0.035), but not with activated partial thromboplastin time-based APC resistance ratios [3].

Psychiatry related information on PROS1

• Measurements of protein C, protein S, and AT III levels were obtained prior to conditioning therapy and weekly thereafter for 2-3 weeks [4].
• Alexia without agraphia following cerebral venous thrombosis associated with protein C and protein S deficiency [5].
• Innovative scales assessed behavioral consequences of urinary dysfunction, sexuality, health worry, PSA concern, perceived cancer control, treatment decision making, decision regret, and cancer-related outlook [6].
• In this study we determined the effect of parenteral testosterone replacement on PSA and PSA velocity in a group of men being treated for erectile dysfunction [7].
• RESULTS: The median time to PSA failure after postoperative RT was 1.34 years for the combined therapy group and 0.97 years for the RT alone group (p = 0.19), with no failures beyond 5 years [8].

High impact information on PROS1

• This article reviews the salient features of PSA, with particular emphasis on strategies to improve its utility in the diagnosis of prostate cancer [9].
• Prostate-specific antigen (PSA) is the most important of all tumor markers in that it has significant applications in all aspects of the management of men with prostatic disease [9].
• If a slightly more specific PSA assay is developed, the higher prevalence of clinically detectable prostate cancer could also make screening less costly than breast cancer screening [10].
• Reporting in this issue of Cell, Kasper and colleagues (Mazmanian et al., 2005) reveal that a bacterial polysaccharide, PSA, produced by the commensal bacterium Bacteroides fragilis directs development of the immune system of the mouse host [11].
• Plasma levels, protein C antigen, protein S antigen, and antithrombin antigen were lower than those in the controls [12].

Chemical compound and disease context of PROS1

• In von Willebrand's disease plasma, which was depleted of protein S, APC did not inactivate Factor VIII [13].
• We carried out serologic measures of thrombophilia (homocysteine, anticardiolipin antibodies [ACLA] immunoglobulin G and immunoglobulin M, lupus anticoagulant, factor VIII, factor XI, protein C, total and free protein S, antithrombin III) and hypofibrinolysis (plasminogen activator inhibitor activity [PAI-Fx], lipoprotein[a]) [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].
• CONCLUSION(S): Serum uric acid levels and plasma protein S activity may be useful as indices of severity of pathology in pregnancy associated hypertension [16].
• Attenuation of norepinephrine-induced release of protein S by pertussis toxin in association with the ADP-ribosylation of a 41,000-D membrane protein indicates that this intracellular transduction pathway involves a regulatory G protein [17].

Biological context of PROS1

• By contrast, no cosegregating PROS1 mutation has been found in any of the six families with only type III phenotypes [18].
• DNA sequence analysis of the protein S gene (PROS1) in 22 Spanish probands with type I or III PS deficiency, has allowed the identification of 10 different mutations and 2 new sequence variants in 15 probands [18].
• Haplotype analysis using 7 microsatellite markers flanking PROS1 was consistent with a common founder for this mutation [19].
• A novel mutation in intron K of the PROS1 gene causes aberrant RNA splicing and is a common cause of protein S deficiency in a UK thrombophilia cohort [1].
• IL-6 exerts its effect through Signal Transducer and Activator of Transcription 3 (STAT3) that interacts with the PROS1 promoter at a binding site in between nucleotides 229 to 207 upstream from the translational start [20].

Anatomical context of PROS1

• Protein S binding to neutrophils decreased approximately twofold in the presence of saturating concentrations of C4bBP [21].
• Two different mapping approaches were used to determine the human chromosomal location of the gene for protein S. A human protein S cDNA was used as a hybridization probe to analyze a panel of somatic cell hybrids containing different human chromosomes [22].
• Free PS has recently been shown to enhance phagocytosis of apoptotic cells by macrophages [23].
• Using Jurkat cells as a model system for apoptosis, we now show protein S to bind to apoptotic cells [24].
• The high recurrence rate (60% spontaneous recurrence) and the relatively high frequency of mesenteric vein thrombosis as a recurrent event favor introduction of long-term oral anticoagulant treatment after the first thrombotic event in patients with a documented hereditary deficiency of AT-III, PC, or PS [25].

Associations of PROS1 with chemical compounds

• Protein S acted by binding to phosphatidylserine expressed on the apoptotic cell surface [26].
• Tumor necrosis factor production during human renal allograft rejection is associated with depression of plasma protein C and free protein S levels and decreased intragraft thrombomodulin expression [27].
• The heavy chain of Factor VIII was cleaved by APC and protein S did not alter the degradation pattern [13].
• In contrast to the other vitamin K-dependent plasma proteins, the COOH-terminal portion of human protein S does not show any resemblance to serine proteases [28].
• A major proportion of C4b-binding protein in plasma is in complex with protein S. The complex is a major and previously unrecognized component of the group of plasma proteins that adsorbs to barium citrate [29].

Physical interactions of PROS1

• C4BP beta chain antigen levels, measured using a new ELISA, averaged 218 nmol/L, a value indistinguishable from the molar concentrations of bound protein S (215 nmol/L) and bound C4BP (227 nmol/L) [30].
• These results allowed us to infer that this method evaluates the ability of protein C to interact with protein S, phospholipids, calcium ions and factor Va [31].
• Activated protein C (APC)-mediated cleavages of factors VIIIa and Va occur on negatively charged phospholipid membranes and involve protein cofactors, protein S and factor V. APC also has anti-inflammatory and anti-apoptotic activities that involve binding of APC to EPCR and cleavage of PAR-1 (protease-activated receptor-1) [32].
• APC-Mie and normal APC bound equally to protein S and to biotinyl-factor Va [33].
• It was also observed that exogenous sIL-6R could also upregulate protein S by forming a complex with IL-6 constitutively produced by the endothelial cell [34].

Enzymatic interactions of PROS1

• VWF-cleaving protease activity (VWF:CP) and protein S (PS) levels (total and free antigen and activity) were within the conventional FFP reference range for test and control CSP [35].

Regulatory relationships of PROS1

• These data show that protein S has an anticoagulant function which is independent of activated protein C and, at least in part, that this is because of its competition with prothrombin for direct binding to Factor Va [36].
• At high tissue-factor concentrations, protein S hardly expressed APC-independent anticoagulant activity but exerted potent APC-cofactor activity when thrombomodulin or APC were added to plasma [37].
• It was suggested that the metabolism of C4bp might be regulated by the plasma PS level, although this hypothesis needs further exploration [38].
• APC inactivates the activated form of coagulation factors V and VIII in the presence of protein S. Administration of APC reduced the pulmonary vascular injury and hypotension as well as the coagulation abnormalities by inhibiting production of the tumor necrosis factor-alpha (TNF-alpha) in rats given endotoxin (ET) [39].
• The thrombin-mediated cleavage of protein S could be inhibited by HPS 7 [40].

Other interactions of PROS1

• Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor [13].
• Four patients had concurrent regulatory protein abnormalities: three protein C deficiencies, one protein S deficiency, and one plasminogen deficiency [41].
• This prediction was recently supported by the demonstration of binding of the PS-C4BP complex to apoptotic cells [42].
• The proteolytic cleavage and subsequent inactivation of recombinant human factor VIII (rhFVIII) and human factor VIIIa (rhFVIIIa) by recombinant human activated protein C (rAPC) was analyzed in the presence and absence of human protein S and human factor V (FV) [43].
• The native and recombinant Gas6, but not protein S, stimulated tyrosine phosphorylation of Sky ectopically expressed in Chinese hamster ovary cells [44].

Analytical, diagnostic and therapeutic context of PROS1

• After treatment of this complex with thrombin, however, the actions of APC and protein S towards Factor VIII were completely restored [13].
• We recently developed an enzyme-linked immunosorbent assay (ELISA) for total protein S (PS) antigen using the monoclonal antibody S-12 [45].
• By contrast, the frequency of the PS Heerlen allele in the group of patients with type III PS deficiency (9 of 46 chromosomes, P = .196) was significantly higher (P < .001) than in the control group (1 of 300 chromosomes, P = .003) [46].
• Platelets of each family member contained the same immunoblotting pattern of normal and variant protein S forms as found in plasma, consistent with the hypothesis that protein S gene expression involves codominant expression of two alleles that is similar in cells that control the synthesis of both platelet and plasma forms of protein S [47].
• In situ hybridization of the protein S cDNA probe to human metaphase chromosomes permitted a precise localization of protein S to the region of chromosome 3 immediately surrounding the centromere (3p11.1----3q11.2) [22].

References