Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of new compounds, 6-amino-1-naphthalenesulfonamides (ANSN), were used as fluorescent detecting groups for substrates of amidases. These compounds have a high quantum fluorescent yield, and the sulfonyl moiety permits a large range of chemical modification. Fifteen ANSN substrates with the structure (N alpha-Z)Arg-ANSNR1R2 were synthesized and evaluated for their reactivity with 8 proteases involved in blood coagulation and fibrinolysis. Thrombin, activated protein C, and urokinase rapidly hydrolyzed substrates with monosubstituted sulfonamide moieties (R1 = H). The maximum rate of substrate homologue). The hydrolysis rates for substrates with branched substituents were slower than their linear analogues. Monosubstituted (N alpha-Z)Arg-ANSNR1R2 possessing cyclohexyl or benzyl groups in the sulfonamide moiety were hydrolyzed by these three enzymes at rates similar to that of the n-butyl homologue (except the cyclohexyl compound for u-PA). Factor Xa rapidly hydrolyzed substrates with short alkyl chains, especially when R1 = R2 = CH3 or C2H5. Lys-plasmin and rt-PA demonstrated low activity with these compounds, and the best results were accomplished for monosubstituted compounds when R2 = benzyl (for both enzymes). Factor VIIa and factor IXa beta exhibited no activity with these substrates. A series of 14 peptidyl ANSN substrates were synthesized, and their reactivity for the same 8 enzymes was evaluated. Thrombin, factor Xa, APC, and Lys-plasmin hydrolyzed all of the substrates investigated. Urokinase, rt-PA, and factor IXa beta exhibited reactivity with a more limited group of substrates, and factor VIIa hydrolyzed only one compound (MesD-LGR-ANSN(C2H5)2). The substrate ZGGRR-ANSNH (cyclo-C6H11) showed considerable specificity for APC in comparison with other enzymes (kcat/KM = 19,300 M-1 s-1 for APC, 1560 for factor IIa, and 180 for factor Xa). This kinetic advantage in substrate hydrolysis was utilized to evaluate the activation of protein C by thrombin in a continuous assay format. Substrate (D-LPR-ANSNHC3H7) was used to evaluate factor IX activation by the factor VIIa/tissue factor enzymatic complex in a discontinuous assay. A comparison between the commercially available substrate chromozyme TH (p-nitroanilide) and the ANSN substrate with the same peptide sequence (TosGPR) demonstrated that aminonaphthalenesulfonamide increased the specificity (kcat/KM) of substrate hydrolysis by thrombin more than 30 times, with respect to factor Xa substrate hydrolysis.
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PMID:Aminonaphthalenesulfonamides, a new class of modifiable fluorescent detecting groups and their use in substrates for serine protease enzymes. 160 66

Suppression of the fibrinolytic activity plays an important role in the prevention of hemorrhage during pregnancy and labor. A hypofibrinolytic and hypercoagulable state may be established in the placenta during pregnancy. However, little infraction is present in the normal placenta. This evidence shows that placenta maintains the fibrinolytic activity in spite of hypercoagulable state. As there is a high amount of APC in the placenta, APC is thought to be involved in fibrinolysis of placenta. Thus, we studied the role of APC on fibrinolysis in placenta. (1) uPA activity of cell membrane reappears after incubation with uPA/PAI-1 complex and a large amount of APC by flow cytometry, (2) APC was made PAI-1/APC complex after incubation of uPA/PAI-1 complex with APC. Our results suggest that APC is the important substance for fibrinolysis in the placenta by decreasing of PAI activity.
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PMID:Relationship of urokinase type plasminogen activator, plasminogen activator inhibitor type 1 and activated protein C in fibrinolysis of human placenta. 911 54

We recently described a subset of peripheral CD14+CD34+ cells able to migrate across endothelial cell monolayers and differentiate into immunostimulatory dendritic cells (DC). In this paper we show that immature DC derived from CD14+CD34+ precursors are also capable of reverse transendothelial migration and extracellular matrix (ECM) invasion using the urokinase plasminogen activator receptor (uPAR). We found that these cells respond to macrophage-inflammatory protein (MIP)-1alpha, enhancing their ability to invade ECM and supporting the idea that immature DC are selectively recruited at the site of inflammation to expand the pool of APCs. Interestingly, MIP-1alpha was also capable of preventing the decreased matrix invasion observed by blocking uPAR, suggesting that the uPA/uPAR system and MIP-1alpha cooperate in driving immature DC migration through the subendothelial matrix. Upon exposure to maturating stimuli, such as TNF-alpha, CD14+CD34+-derived DC enhance their APC function and decrease the capacity of invading ECM; these changes are accompanied by altered expression and function of uPAR. Moreover, mature DC shift their sensitivity from MIP-1alpha to MIP-3beta, enhancing their transendothelial migration capability in response to the latter chemokine. Our data support the hypothesis that bloodborne DC can move through ECM toward the site of pathogen entry where they differentiate into fully mature APCs with their motility and function regulated by microenvironmental stimuli, including MIP-1alpha, MIP-3beta, and TNF-alpha.
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PMID:uPA/uPAR system is active in immature dendritic cells derived from CD14+CD34+ precursors and is down-regulated upon maturation. 1062 14

Invasion and dissemination of well-differentiated carcinomas are often associated with loss of epithelial differentiation and gain of mesenchymal-like capabilities of dedifferentiated tumor cells at the invasive front. However when analysing central areas of metastases of colorectal carcinomas one finds a regain of the differentiated epithelial growth patterns like in the primary tumor. More than 80% of these tumor have loss of function mutations in the APC tumor suppressor gene, leading to an overexpression of beta-catenine. In its nuclear pool beta-catenine acts as a transcription factor and is now considered as one of the main oncogenic proteins in colorectal carcinogenesis. We could define several molecules important for the processes of invasion and dissemination, like MMP-7, uPA, laminin-5, as target genes activated by nuclear beta-catenine. Moreover the characteristic phenotypic changes during tumor progression were associated with distinct expression patterns of beta-catenine and E-cadherin. Nuclear beta-catenine was found in dedifferentiated mesenchyme-like tumor cells at the invasive front, but strikingly, like in central areas of the primary tumors, was localized to the membrane and cytoplasm in polarized epithelial tumor cells in the metastases. This was accompanied by changes in the proliferative activity. Based on these data, we postulate that an important driving force for progression of well-differentiated colorectal carcinomas is the specific environment, initiating two transient phenotypic transition processes by modulating intracellular beta-catenine distribution in the tumor cells.
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PMID:[The Rudolf Virchow Prize 2001. The role of the oncoprotein beta-catenin ni the progression of colorectal cancers]. 1189 5

The serine protease tryptase has been associated with a broad range of allergic and inflammatory diseases and, in particular, has been implicated as a critical mediator of asthma. The inhibition of tryptase therefore has the potential to be a valuable therapy for asthma. The synthesis, employing solution phase parallel methods, and SAR of a series of novel 2-azepanone tryptase inhibitors are presented. A member of this series, 8t, was identified as a potent inhibitor of human tryptase (IC(50)=38 nM) with selectivity >/=330-fold versus related serine proteases (trypsin, plasmin, uPA, tPA, APC, alpha-thrombin, and FXa) [corrected].
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PMID:Synthesis of potent and selective 2-azepanone inhibitors of human tryptase. 1469 47