Project description:<p>Livestock diseases caused by Trypanosoma congolense, T. vivax and T. brucei, collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under veterinary development. Here, we show that the most efficacious subclass of these compounds are prodrugs activated by trypanosome serine carboxypeptidases (CBPs). Drug-resistance to a development candidate, AN11736, emerged readily in T. brucei, due to partial deletion within the locus containing three tandem copies of the CBP genes. T. congolense parasites, which possess a larger array of related CBPs, also developed resistance to AN11736 through deletion within the locus. A genome-scale screen in T. brucei confirmed CBP loss-of-function as the primary mechanism of resistance and CRISPR-Cas9 editing proved that partial deletion within the locus was sufficient to confer resistance. CBP re-expression in either T. brucei or T. congolense AN11736-resistant lines restored drug-susceptibility. CBPs act by cleaving the benzoxaborole AN11736 to a carboxylic acid derivative, revealing a prodrug activation mechanism. Loss of CBP activity results in massive reduction in net uptake of AN11736, indicating that entry is facilitated by the concentration gradient created by prodrug metabolism.</p><p><br></p><p><strong>T. brucei assay</strong> is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS1474' rel='noopener noreferrer' target='_blank'><strong>MTBLS1474</strong></a>.</p><p><strong>T. congolense assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1309' rel='noopener noreferrer' target='_blank'><strong>MTBLS1309</strong></a>.</p><p><br></p><p><strong>Linked cross omic data sets:</strong></p><p>Genome data associated with this study are available in the European Nucleotide Archive (ENA): accession number <a href='https://www.ebi.ac.uk/ena/browser/view/PRJEB34627' rel='noopener noreferrer' target='_blank'>PRJEB34627</a>.</p>
Project description:<p>Livestock diseases caused by Trypanosoma congolense, T. vivax and T. brucei, collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under veterinary development. Here, we show that the most efficacious subclass of these compounds are prodrugs activated by trypanosome serine carboxypeptidases (CBPs). Drug-resistance to a development candidate, AN11736, emerged readily in T. brucei, due to partial deletion within the locus containing three tandem copies of the CBP genes. T. congolense parasites, which possess a larger array of related CBPs, also developed resistance to AN11736 through deletion within the locus. A genome-scale screen in T. brucei confirmed CBP loss-of-function as the primary mechanism of resistance and CRISPR-Cas9 editing proved that partial deletion within the locus was sufficient to confer resistance. CBP re-expression in either T. brucei or T. congolense AN11736-resistant lines restored drug-susceptibility. CBPs act by cleaving the benzoxaborole AN11736 to a carboxylic acid derivative, revealing a prodrug activation mechanism. Loss of CBP activity results in massive reduction in net uptake of AN11736, indicating that entry is facilitated by the concentration gradient created by prodrug metabolism.</p><p><br></p><p><strong>T. congolense assay</strong> is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS1309' rel='noopener noreferrer' target='_blank'><strong>MTBLS1309</strong></a>.</p><p><strong>T. brucei assay</strong> is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS1474' rel='noopener noreferrer' target='_blank'><strong>MTBLS1474</strong></a>.</p><p><br></p><p><strong>Linked cross omic data sets:</strong></p><p>Genome data associated with this study are available in the European Nucleotide Archive (ENA): accession number <a href='https://www.ebi.ac.uk/ena/browser/view/PRJEB34627' rel='noopener noreferrer' target='_blank'>PRJEB34627</a>.</p>
Project description:Effect of expression of dipeptidyl peptidase-IV (DPP-IV) in U373 cell line on uncontrolled cell proliferation and aberrant interactions with the brain extracellular matrix.
Project description:Recent studies showed epithelial-mesenchymal transition (EMT) is involved in cancer progression. Though we revealed that downregulation of ΔNp63 in oral squamous cell carcinoma (OSCC) induces EMT, the detailed molecular mechanisms remain to be elucidated. DNA microarray analyses were thus performed by using OSCC cell line overexpressing ΔNp63 to examine the genes associated with EMT. The results revealed that kallikrein related peptidase 6 (KLK6) was most upregulated in the OSCC cells overexpressing ΔNp63.
Project description:Signal peptide peptidase (SPP) plays an essential role in among all eukaryotes. The knock out lines of A. thaliana SPP (AtSPP) is lethal and the substrates of AtSPP are not identified. Based on the situation, we constructed the plants with AtSPP over-expressed and knock down to investigate the role of AtSPP. We also used the data to find the candidate substrates of AtSPP, which regulates intermembrane proteolysis, would have crucial physiological functions as well as control the gene expression encoding the substrates.