Project description:Ibuprofen, an inhibitor of prostanoid biosynthesis is the most common pharmacological agent used for the management of pain, inflammation and fever. However, the chronic use of ibuprofen at high doses is associated with increased risk for cardiovascular, renal, gastrointestinal and liver injuries. The underlying mechanisms of ibuprofen-mediated effects on mice liver and proteasome function remain unclear. To determine the mechanisms and pathways affected by ibuprofen treatment (100mg/kg for 7 days), we performed proteomic profiling of male mice liver with quantitative LC-MS/MS using ten-plex tandem mass tag (TMT) labeling. More than 300 proteins were significantly altered between the control and ibuprofen-treated groups. Independent validation of proteomic data by Western blotting was carried out on 14 proteins using both male and female samples. Additional proteasome and immunoproteasome activity/expression was assayed to evaluate differences in proteasome function between male and female mice liver. Our data suggests that these differentially expressed proteins were found to be associated with several major pathways including (1) energy metabolism, (2) protein degradation, (3) fatty acid synthesis and (4) anti-oxidant system. The study suggests that the sex-related differences in the energy metabolism and proteasome dysfunction are underlying mechanisms for ibuprofen-mediated effects in mice liver and provide insights on novel molecular targets for future drug discovery and development.
2019-06-17 | MSV000083987 | MassIVE
Project description:To determine the differentially expressed genes in cancer associated fibroblasts upon knockdown of ACLP.
Project description:We report whole genome chromatin immunoprecipitation followed by sequencing (ChIP-seq) of 3 different RNA Pol II CTD modifications in MCF-7 breast cancer cells treated with vehicle (UNTR) or the proteasome inhibitor MG132 for 4 (MG4H) or 24 (MG24H) hours. We find the non-phosphorylated form of RNA Pol II CTD accumulates at TSS of all expressed genes in proteasome inhibited cells, particularly after 24H of MG132 treatment. Proteasome inhibition enhances Ser5-P and Ser2-P binding at TSS of genes induced by MG132. We note that proteasome inhibition establishes unique Ser2-P 5’ to 3’ gene profiles at induced compared to repressed genes. Overall proteasome inhibition enhances RNA Pol II processivity and expression of gene networks relevant to breast cancer. The study provides a comprehensive resource of RNA Pol II binding in proteasome inhibited cells.
Project description:We used a chemical library to screen for cytotoxic compounds with Michael acceptor groups that induce a cellular response characteristic of proteasome inhibition. We then determined the differentially expressed genes in MCF7 cells following treatment with each of the identified hits This dataset includes expression data from MCF7 cells treated with either DMSO or one of the treatment compounds
Project description:We used microarrays to detail the global programme of gene expression in lung SCC cells treated with belinostat, a pan-HDAC inhibitor. The primary focus of this work is to investigate the efficacy of belinostat on lung SCC cells. Our phosphoproteomic profiling analyses revealed the downregulation of MAPK signaling pathway upon drug treatment, together with the induction of apoptosis. While HDAC inhibition generally affects transcription, the mechanism of SOS/MAPK downregulation was therefore proposed to be affected at the transcriptomic level. However, genes related to MAPK pathway were not significantly regulated upon belinostat treatment, whereas ubiquitin-proteasome gene signature was affected. This supports an indirect mechanism of epigenetic regulation on MAPK signaling that should be explored further.