Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evading apoptosis is a cancer hallmark that remains a serious obstacle in current treatment approaches. Although proteasome inhibitors (PIs) have transformed management of multiple myeloma (MM), drug resistance emerges through induction of the aggresome+autophagy pathway as a compensatory protein clearance mechanism. Genome-wide profiling identified microRNAs (miRs) differentially expressed in bortezomib-resistant myeloma cells compared with drug-naive cells. The effect of individual miRs on proteasomal degradation of short-lived fluorescent reporter proteins was then determined in live cells. MiR-29b was significantly reduced in bortezomib-resistant cells as well as in cells resistant to second-generation PIs carfilzomib and ixazomib. Luciferase reporter assays demonstrated that miR-29b targeted PSME4 that encodes the proteasome activator PA200. Synthetically engineered miR-29b replacements impaired the growth of myeloma cells, patient tumor cells and xenotransplants. MiR-29b replacements also decreased PA200 association with proteasomes, reduced the proteasome's peptidase activity and inhibited ornithine decarboxylase turnover, a proteasome substrate degraded through ubiquitin-independent mechanisms. Immunofluorescence studies revealed that miR-29b replacements enhanced the bortezomib-induced accumulation of ubiquitinated proteins but did not reveal aggresome or autophagosome formation. Taken together, our study identifies miR-29b replacements as the first-in-class miR-based PIs that also disrupt the autophagy pathway and highlight their potential to synergistically enhance the antimyeloma effect of bortezomib.
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PMID:MiR-29b replacement inhibits proteasomes and disrupts aggresome+autophagosome formation to enhance the antimyeloma benefit of bortezomib. 2523 65

By comparing differentially abundant proteins and metabolites, the protein expression, metabolic changes and metabolic regulation mechanisms during the priming phase of liver regeneration (LR) were investigated. We combined proteomic analysis via isobaric tags for relative and absolute quantification (iTRAQ) with metabolomic analysis via nontargeted liquid chromatography-mass spectrometry (LC-MS). LC-MS was used to examine 29 energy metabolites expression alterations in targeted metabolomics. A total number of 441 differentially expressed proteins and 65 metabolites were identified. PSMB10, PSMB5, RCG_63409, PSME4 and PSMB7 were key node proteins, these proteins are involved in the proteasome pathway. The most strongly enriched transcription factor motif was TP63. These results point out a critical role of the proteasome pathway (defense mechanisms) and of TP63 (metabolic regulator) as the key transcription factor during the priming phase of LR. Metabolomic and metabolite analysis showed that profiling indicates upregulation of arginine biosynthesis and glycolysis as the main ATP-delivering pathway. Integrative proteomic and metabolomic analysis showed that biomolecular changes were primarily related to the neurological disease, cell death and survival and cell morphology. What's more, neurotransmitters may play an important role in the regulation of LR.
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PMID:A combined proteomic and metabolomic analyses of the priming phase during rat liver regeneration. 3289 68