Search results for " Regulation"
showing 10 items of 3187 documents
Dominant role of paraoxonases in inactivation of the Pseudomonas aeruginosa quorum-sensing signal N-(3-oxododecanoyl)-L-homoserine lactone.
2008
Pseudomonas aeruginosa is an opportunistic bacterium which causes serious infections in immunocompromised and cystic fibrosis patients (10). As with many gram-negative bacteria, P. aeruginosa produces acyl-homoserine lactone (AHL) quorum-sensing (QS) signaling molecules termed autoinducers which allow the single-celled organisms to coordinate their actions (36). N-(3-Oxododecanoyl)-l-homoserine lactone (3OC12-HSL) is a key autoinducer synthesized by P. aeruginosa which regulates the expression of extracellular virulence factors and biofilm formation (5, 36). Rats and mice experimentally infected with P. aeruginosa mutants deficient in the ability to produce or respond to 3OC12-HSL exhibited…
Morpholino knockdown of the ubiquitously expressed transmembrane serine protease TMPRSS4a in zebrafish embryos exhibits severe defects in organogenes…
2011
AbstractOver the past years the members of the type II transmembrane serine protease (TTSP) family have emerged as new players in mammalian biology. TMPRSS4 (transmembraneprotease/serine) is overexpressed in several human cancer tissues, promoting invasion, migration, and metastasis. However, the physiological function has not yet been elucidated. Here, we present morpholino knockdown studies targeting TMPRSS4a, a homolog of human TMPRSS4 in zebrafish embryos. By RT-PCR, we could demonstrate an expression of this protease already 5 h post-fertilization, suggesting important functions in the early stages of embryonic development. Indeed,in vivogene silencing caused severe defects in tissue d…
Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases
2019
The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and inhibition were determined to establish them as new lead compounds for flaviviral inhibitors. Based on our structure-activity relationship studies, the molecules were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric binding site in the proteases was probed using mutagenesis and covalent modificati…
SAR of novel benzothiazoles targeting an allosteric pocket of DENV and ZIKV NS2B/NS3 proteases
2021
In recent years, dengue virus (DENV) and Zika virus (ZIKV), both mosquito-borne members of the Flaviviridae family, have emerged as intercontinental health issues since their vectors have spread from their tropical origins to temperate climate zones due to climate change and increasing globalization. DENV and ZIKV are positive-sense, single-stranded RNA viruses, whose genomes consist of three structural (capsid, membrane precursor, envelope) and seven non-structural (NS) proteins, all of which are initially expressed as a single precursor polyprotein. For virus maturation, the polyprotein processing is accomplished by host proteases and the viral NS2B/NS3 protease complex, whose inhibitors …
Bortezomib Partially Improves Laminin α2 Chain–Deficient Muscular Dystrophy
2014
Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measu…
Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1
2001
Glucocorticoids inhibit the proinflammatory activities of transcription factors such as AP-1 and NF-kappa B as well as that of diverse cellular signaling molecules. One of these signaling molecules is the extracellular signal-regulated kinase (Erk-1/2) that controls the release of allergic mediators and the induction of proinflammatory cytokine gene expression in mast cells. The mechanism of inhibition of Erk-1/2 activity by glucocorticoids is unknown. Here we report a novel dual action of glucocorticoids for this inhibition. Glucocorticoids increase the expression of the MAP kinase phosphatase-1 (MKP-1) gene at the promoter level, and attenuate proteasomal degradation of MKP-1, which we re…
The Cleavage Product of Amyloid-β Protein Precursor sAβPPα Modulates BAG3-Dependent Aggresome Formation and Enhances Cellular Proteasomal Activity
2015
Alzheimer's disease (AD) is the major age-associated form of dementia characterized by gradual cognitive decline. Aberrant cleavage of the amyloid-β protein precursor (AβPP) is thought to play an important role in the pathology of this disease. Two principal AβPP processing pathways exist: amyloidogenic cleavage of AβPP resulting in production of the soluble N-terminal fragment sAβPPβ, amyloid-β (Aβ), which accumulates in AD brain, and the AβPP intracellular domain (AICD) sAβPPα, p3 and AICD are generated in the non-amyloidogenic pathway. Prevalence of amyloidogenic versus non-amyloidogenic processing leads to depletion of sAβPPα and an increase in Aβ. Although sAβPPα is a well-accepted neu…
The molecular heterogeneity of hemocyanin: Structural and functional properties of the 4×6-meric protein of Upogebia pusilla (Crustacea)
2006
The structural properties of the hemocyanin isolated from the Mediterranean mud shrimp, Upogebia pusilla (Decapoda: Thalassinidea), were investigated. Our intent was to make use of the U. pusilla case to perform a structural comparison between crustacean and chelicerate 4×6-meric hemocyanins. The thalassinidean hemocyanin appears similar in size but different in structural organization compared to the chelicerate 4×6-mer. Ultracentrifuge analyses on the purified protein revealed a sedimentation coefficient of 39S, typical of 4×6 hemocyanins. Electron micrographs are in agreement with a model in which four 2×6-meric building blocks are arranged in a tetrahedron-like quaternary structure and …
The Transporter Associated With Antigen Processing (TAP): Structural Integrity, Expression, Function, and Its Clinical Relevance
2001
BACKGROUND: The transporter associated with antigen processing (TAP), a member of the family of ABC transporters, plays a crucial role in the processing and presentation of the major histocompatibility complex (MHC) class I restricted antigens. TAP transports peptides from the cytosol into the endoplasmic reticulum, thereby selecting peptides matching in length and sequence to respective MHC class I molecules. Upon loading on MHC class I molecules, the trimeric MHC class I/beta2-microglobulin/ peptide complex is then transported to the cell surface and presented to CD8+ cytotoxic T cells. Abnormalities in MHC class I surface expression have been found in a number of different malignancies, …
Broad Spectrum Thiopeptide Recognition Specificity of theStreptomyces lividans TipAL Protein and Its Role in Regulating Gene Expression
1999
Microbial metabolites isolated in screening programs for their ability to activate transcription of the tipA promoter (ptipA) in Streptomyces lividans define a class of cyclic thiopeptide antibiotics having dehydroalanine side chains ("tails"). Here we show that such compounds of heterogeneous primary structure (representatives tested: thiostrepton, nosiheptide, berninamycin, promothiocin) are all recognized by TipAS and TipAL, two in-frame translation products of the tipA gene. The N-terminal helix-turn-helix DNA binding motif of TipAL is homologous to the MerR family of transcriptional activators, while the C terminus forms a novel ligand-binding domain. ptipA inducers formed irreversible…