Search results for "proteasome"
showing 10 items of 145 documents
MYC and EGR1 synergize to trigger tumor cell death by controlling NOXA and BIM transcription upon treatment with the proteasome inhibitor bortezomib
2014
The c-MYC (MYC afterward) oncogene is well known for driving numerous oncogenic programs. However, MYC can also induce apoptosis and this function of MYC warrants further clarification. We report here that a clinically relevant proteasome inhibitor significantly increases MYC protein levels and that endogenous MYC is necessary for the induction of apoptosis. This kind of MYC-induced cell death is mediated by enhanced expression of the pro-apoptotic BCL2 family members NOXA and BIM. Quantitative promoter-scanning chromatin immunoprecipitations (qChIP) further revealed binding of MYC to the promoters of NOXA and BIM upon proteasome inhibition, correlating with increased transcription. Both pr…
Synthesis of C3/C1-Substituted Tetrahydroisoquinolines
2015
A broad biological screening of the natural alkaloid N-methylisosalsoline (2) extracted from Hammada scoparia leaves against a panel of human and parasitic proteases revealed an interesting activity profile of 2 towards human 20S proteasome. This outcome suggests that the 1,2,3,4-tetrahydroisoquinoline skeleton may be exploited as a template for the development of novel anticancer agents. In this article, we report the synthesis and chemical characterization of a new series of isosalsoline-type alkaloids (10-11) with variations at N2 and C3 positions with respect to the natural Compound 2, obtained by a synthetic strategy that involves the Bischler-Napieralski cyclization. The substrate for…
Antiproliferative Properties of a Few Auranofin-Related Gold(I) and Silver(I) Complexes in Leukemia Cells and their Interferences with the Ubiquitin …
2020
A group of triethylphosphine gold(I) and silver(I) complexes, structurally related to auranofin, were prepared and investigated as potential anticancer drug candidates. The antiproliferative properties of these metal compounds were assessed against two leukemia cell lines, i.e., CCRF-CEM and its multidrug-resistant counterpart, CEM/ADR5000. Interestingly, potent cytotoxic effects were disclosed for both series of compounds against leukemia cells, with IC50 values generally falling in the low-micromolar range, the gold derivatives being on the whole more effective than the silver analogues. Some initial structure-function relationships were drawn. Subsequently, the ability of the study compo…
Cryo-negative staining
1998
Abstract A procedure is presented for the preparation of thin layers of vitrified biological suspensions in the presence of ammonium molybdate, which we termcryo-negative staining. The direct blotting of sample plus stain solution on holey carbon supports produces thin aqueous films across the holes, which are routinely thiner than the aqueous film produced by conventional negative staining on a continuous carbon layer. Because of this, a higher than usual concentration of negative stain (ca. 16% rather than 2%) is required for cryo-negative staining in order to produce an optimal image contrast. The maintenance of the hydrated state, the absence of adsorption to a carbon film and associate…
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…
Analysis of the MHC Class I Antigen Presentation Machinery in Human Embryonal Carcinomas: Evidence for Deficiencies in TAP, LMP and MHC Class I Expre…
1998
The expression of the major histocompatibility complex (MHC) class I antigens is suppressed in early post-implantation embryonic cells as well as in embryonal carcinoma (EC) cells, but could be upregulated by treatment with interferon (IFN)-gamma or retinoic acid. In a number of human and murine tumours, defects in the expression of the different components of the MHC class I antigen processing machinery, such as the proteasomal subunits LMP-2 and LMP-7 and the peptide transporters TAP-1 and TAP-2, account for impaired MHC class I surface expression. Here, we analysed the constitutive and IFN-gamma regulated mRNA and protein expression of the LMP, TAP and MHC class I molecules in the human …
Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation
2001
Dendritic cells (DC) are professional antigen-presenting cells (APC) which proceed from immature to a mature stage during their final differentiation. Immature DC are highly effective in terms of antigen uptake and processing, whereas mature DC become potent immunostimulatory cells. Until now, the expression profiles of the major components of the MHC class I antigen-processing machinery (APM) during DC development have not been well characterized. In this study, the mRNA and protein expression levels of the IFN-gamma inducible proteasome subunits, of the proteasome activators PA28, and of key components required for peptide transport and MHC class I-peptide complex assembly have been evalu…
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…
Special Issue on “Proteostasis and Autophagy”
2019
Autophagy is a highly conserved eukaryotic pathway responsible for the lysosomal degradation (and subsequent recycling) of cellular components such as proteins, protein aggregates, and a growing number of organelles or cellular compartments [...]
Multi-output Model with Box-Jenkins Operators of Quadratic Indices for Prediction of Malaria and Cancer Inhibitors Targeting Ubiquitin- Proteasome Pa…
2016
The ubiquitin-proteasome pathway (UPP) is the primary degradation system of short-lived regulatory proteins. Cellular processes such as the cell cycle, signal transduction, gene expression, DNA repair and apoptosis are regulated by this UPP and dysfunctions in this system have important implications in the development of cancer, neurodegenerative, cardiac and other human pathologies. UPP seems also to be very important in the function of eukaryote cells of the human parasites like Plasmodium falciparum, the causal agent of the neglected disease Malaria. Hence, the UPP could be considered as an attractive target for the development of compounds with Anti-Malarial or Anti-cancer properties. R…