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)

Fetal Alcohol Spectrum Disorders (FASD) are birth defects that result from maternal alcohol use. We used a non a priori approach to prioritize candidate pathways during alcohol-induced teratogenicity in early mouse embryos. Two C57BL/6 substrains (B6J, B6N) served as the basis for study. Dosing pregnant dams with alcohol (2x 2.9 g/kg ethanol spaced 4 hr on day 8) induced FASD in B6J at a higher incidence than B6N embryos. Counter-exposure to PK11195 (4 mg/kg) significantly protected B6J embryos but slightly promoted FASD in B6N embryos. Microarray transcript profiling was performed on the embryonic headfold 3 hr after the first maternal alcohol injection (GEO data series accession GSE1074). This analysis revealed metabolic and cellular reprogramming that was substrain-specific and/or PK11195-dependent. Mapping ethanol-responsive KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways revealed down-regulation of ribosomal proteins and proteasome, and up-regulation of glycolysis and pentose phosphate pathway in B6N embryos; and significant up-regulation of tight junction, focal adhesion, adherens junction, and regulation of the actin cytoskeleton (and near-significant up-regulation of Wnt signaling and apoptosis) pathways in both substrains. Expression networks constructed computationally from these altered genes identified entry points for EtOH at several hubs (MAPK1, ALDH3A2, CD14, PFKM, TNFRSF1A, RPS6, IGF1, EGFR, PTEN) and for PK11195 at AKT1. Our findings are consistent with the growing view that developmental exposure to alcohol alters common signaling pathways linking receptor activation to cytoskeletal reorganization. The programmatic shift in cell motility and metabolic capacity further implies cell signals and responses that are integrated by the mitochondrial recognition site for PK11195.
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PMID:Reprogramming of genetic networks during initiation of the Fetal Alcohol Syndrome. 1720 Sep 51

Multiple myeloma (MM) is a remarkable example of rapid bench-to-bedside translation in new drug development. The proteasome inhibitor bortezomib and immunomodulatory drug lenalidomide targeted MM cells in the bone marrow (BM) microenvironment to overcome conventional drug resistance in laboratory and animal models and were rapidly translated into clinical trials demonstrating their efficacy in patients with relapsed and then newly diagnosed MM, with a doubling of the median survival as a direct result. The future is even brighter. First, immune-based therapies are being developed (eg, elotuzumab monoclonal antibody [MoAb]; CD138DM immunotoxin; MM cell-dendritic cell vaccines; CD138, CS-1, and XBP-1 peptide vaccines; anti-17 MoAb; and other treatments to overcome causes of immune dysfunction). Second, promising next-generation agents target the MM cell in its microenvironment (eg, deubiquitinating enzyme inhibitors; chymotryptic [carfilzomib, Onyx 0912, MLN 9708] and broader [NPI-0052] proteasome inhibitors; immunoproteasome inhibitors; and pomalidamide). Moreover, agents targeting bone biology (eg, zoledronic acid, anti-DKK-1 MoAb, anti-B-cell activating factor MoAb and bortezomib, Btk inhibitor) show promise not only in preserving bone integrity but also against MM. Third, rationally based combination therapies, including bortezomib with Akt, mammalian target of rapamycin, or histone deacetylase inhibitors, are active even in bortezomib-refractory MM. Finally, genomics is currently being used in the definition of MM heterogeneity, new target discovery, and development of personalized therapy. Myeloma therefore represents a paradigm for targeting the tumor in its microenvironment, which has already markedly improved patient outcome in MM and has great potential in other hematologic malignancies and solid tumors as well.
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PMID:The 39th David A. Karnofsky Lecture: bench-to-bedside translation of targeted therapies in multiple myeloma. 2221 54

N-glycanase 1 (NGLY1) Deficiency is a rare monogenic multi-system disorder first described in 2014. NGLY1 is evolutionarily conserved in model organisms. Here we conducted a natural history study and chemical-modifier screen on the Drosophila melanogaster NGLY1 homolog, Pngl We generated a new fly model of NGLY1 Deficiency, engineered with a nonsense mutation in Pngl at codon 420 that results in a truncation of the C-terminal carbohydrate-binding PAW domain. Homozygous mutant animals exhibit global development delay, pupal lethality and small body size as adults. We developed a 96-well-plate, image-based, quantitative assay of Drosophila larval size for use in a screen of the 2,650-member Microsource Spectrum compound library of FDA approved drugs, bioactive tool compounds, and natural products. We found that the cholesterol-derived ecdysteroid molting hormone 20-hydroxyecdysone (20E) partially rescued the global developmental delay in mutant homozygotes. Targeted expression of a human NGLY1 transgene to tissues involved in ecdysteroidogenesis, e.g., prothoracic gland, also partially rescues global developmental delay in mutant homozygotes. Finally, the proteasome inhibitor bortezomib is a potent enhancer of global developmental delay in our fly model, evidence of a defective proteasome "bounce-back" response that is also observed in nematode and cellular models of NGLY1 Deficiency. Together, these results demonstrate the therapeutic relevance of a new fly model of NGLY1 Deficiency for drug discovery and gene modifier screens.
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PMID:Defects in the Neuroendocrine Axis Contribute to Global Development Delay in a Drosophila Model of NGLY1 Deficiency. 3062 22