Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The non-structural (NS)5A protein of hepatitis C virus (HCV) is cleaved, after translation, by the NS3-encoded zinc-dependent serine proteinase, from the NS4B protein upstream and the NS5B protein downstream. The released, mature NS5A protein is a 56 000 MW phosphoprotein (p56), which also exists within infected cells in a hyperphosphorylated form (p58). The NS5A gene has a quasispecies distribution, meaning that various NS5A sequences co-exist, in various proportions, in infected individuals. HCV NS5A appears to be located in cytoplasmic membranes surrounding the nucleus. Its precise functions are not known. HCV non-structural proteins, including NS5A, form a large multiprotein replication complex, which probably directs the replication of the HCV genome. HCV NS5A lacking the 146 N-terminal amino acids is a potent transcriptional activator in vitro. NS5A can also bind to single-strand RNA-dependent protein kinase (PKR) and inhibit its antiviral function. An 'interferon (IFN) sensitivity-determining region' has recently been postulated in the NS5A protein central region in hepatitis C virus (HCV) genotype 1b, but strongly conflicting evidence has been published. In fact, there would seem to be no such region in the NS5A protein, even though NS5A plays an important and complex role in HCV resistance to IFN. Structure-function studies are required to identify precisely how NS5A and IFN interact.
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PMID:The non-structural 5A protein of hepatitis C virus. 1060 50

The hepatitis C virus (HCV) protease genes (NS2/3 and NS3) were expressed in yeast with their natural substrates fused to a ligand-dependent transcriptional activator, the retinoic acid receptor (RARbeta). RARbeta can activate transcription in yeast cells in response to retinoic acids. We hypothesized that cis-cleavage at the NS2-3 or NS3-4A junctions by the appropriate HCV proteases would release RARbeta, thereby activating transcription of a reporter gene. Our results from Western blot analyses and reporter gene activation indicate that the wild-type NS2/3 and NS3 enzymes are catalytically active in yeast cells, whereas mutations in the catalytic domain of NS2(C993V) and NS3(S1165A) lead to inactive enzymes. We conclude that HCV NS2/3 and NS3 protease activities can be reconstituted in yeast.
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PMID:Reconstitution of hepatitis C virus protease activities in yeast. 1151 46

It is well known that NS3/4A protein plays crucial roles in the hepatitis C virus (HCV) replication. NS3/4A protein also results to virus-mediated immune evasion and persistence of infection through the interaction with host proteins. However, the lack of a suitable animal model hampers studies of HCV NS3/4A protein interaction with host proteins, which impacts immunopathology due to infection. Here, transgenic vector containing transcriptional regulation and Fluc reporter gene was constructed to conditionally express NS3/4A protein under the dual control of Tet-On regulatory system and Cre/LoxP gene-knockout system. NS3/4A transgenic founder mice were continuously crossed with Lap transgenic mice expressing reverse tetracycline-controlled transcriptional activator (rtTA), the NS3/4A/Lap double transgenic mouse lines with liver-specifically and conditionally expressing reporter (luciferase Fluc) under control of Tet-On system were established. The NS3/4A/Lap double transgenic mouse are mated with Lap/LC-1 double transgenic mouse with liver-specifically and conditionally expressing Cre recombinase under control of Tet-On system, NS3/4A/Lap/LC-1 triple transgenic mouse were generated. In vivo bioluminescent imaging, western blotting and immunohistochemical staining (IHS) was used to confirm that NS3/4A protein was strictly expressed in the liver of Doxycycline-induced triple transgenic mice. The results show that we established a triple-transgenic mouse model conditionally expressing the HCV NS3/4A protein under strict control of the Tet-On regulatory system and Cre/loxP system. This novel transgenic mouse model expressing NS3/4A in a temporally and spatially-specific manner will be useful for studying interactions between HCV NS3/4A protein and the host, also for evaluating NS3/4A protease inhibitors.
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PMID:Establishment of a novel triple-transgenic mouse: conditionally and liver-specifically expressing hepatitis C virus NS3/4A protease. 2520 Apr 33