Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Objective- Genome-wide association studies have revealed a robust association between genetic variation on chromosome 15q26.1 and coronary artery disease (CAD) susceptibility; however, the underlying biological mechanism is still unknown. The lead CAD-associated genetic variant (rs17514846) at this locus resides in the FURIN gene. In advanced atherosclerotic plaques, furin is expressed primarily in macrophages. We investigated whether this CAD-associated variant alters FURIN expression and whether furin affects monocyte/macrophage behavior. Approach and Results- A quantitative reverse transcription polymerase chain reaction analysis showed that leukocytes from individuals carrying the CAD risk allele (A) of rs17514846 had increased FURIN expression. A chromatin immunoprecipitation assay revealed higher RNA polymerase II occupancy in the FURIN gene in mononuclear cells of individuals carrying this allele. A reporter gene assay in transiently transfected monocytes/macrophages indicated that the CAD risk allele had higher transcriptional activity than the nonrisk allele (C). An analysis of isogenic monocyte cell lines created by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that isogenic cells with the A/A genotype for rs17514846 had higher FURIN expression levels than the isogenic cells with the C/C genotype. An electrophoretic mobility shift assay exhibited preferential binding of a nuclear protein to the risk allele. Studies of monocytes/macrophages with lentivirus-mediated furin overexpression or shRNA (short hairpin RNA)-induced furin knockdown showed that furin overexpression promoted monocyte/macrophage migration, increased proliferation, and reduced apoptosis whereas furin knockdown had the opposite effects. Conclusions- Our study shows that the CAD-associated genetic variant increases FURIN expression and that furin promotes monocyte/macrophage migration and proliferation while inhibiting apoptosis, providing a biological mechanism for the association between variation at the chromosome 15q26.1 locus and CAD risk.
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PMID:Influence of a Coronary Artery Disease-Associated Genetic Variant on FURIN Expression and Effect of Furin on Macrophage Behavior. 2997 68

Human parainfluenza virus type 3 (HPIV3) causes the majority of childhood viral pneumonia around the world. Fusing the viral and target cell membranes is crucial for its entry into target cells, and the fusion process requires the concerted actions of two viral glycoproteins: hemagglutinin-neuraminidase (HN) and fusion (F) protein. After binding to the cell surface receptor, sialic acids, HN triggers F to undergo large conformational rearrangements to execute the fusion process. Although it has been reported that several domains of F had important impacts on regulating the membrane fusion activity, what role the DI-DII linker (residues 369-374, namely L1 linker) of the HPIV3 F protein plays in the fusion process still remains confused. We have obtained three chimeric mutant proteins (Ch-NDV-L1, Ch-MV-L1, Ch-HPIV1-L1) containing the full length of HPIV3 F protein but their corresponding DI-DII linker derived from the F protein of Newcastle disease virus (NDV), Measles virus (MV), and Human parainfluenza virus type 1 (HPIV1), respectively. One deletion mutant protein (De-L1), whose DI-DII linker was deleted, has been established simultaneously. Then vaccinia virus-T7 RNA polymerase transient expression system and standard plasmid system were utilized to express the mutant F proteins in BHK-21 cells. These four mutants were determined for membrane fusogenic activity, cell surface expression level, and total mutant F protein expression. All of them resulted in a significant reduction in fusogenic activity in all steps of cell-cell membrane fusion process. There was no significant difference in cell surface protein expression level for the mutants compared with wild-type F. The mutant proteins with inability in fusogenic activity were all at the form of precursor protein, F0, which were not hydrolyzed by intracellular protease furin. The results above suggest that the involvement of the DI-DII linker region is necessary for the complete fusion of the membranes.
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PMID:The DI-DII linker of human parainfluenza virus type 3 fusion protein is critical for the virus. 3176 10


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