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)

Proteasomes and mitochondrial membrane changes are involved in thymocyte apoptosis. The hierarchical relationship between protease activation and mitochondrial alterations has been elusive. Here we show that inhibition of proteasomes by two specific agents, lactacystin or MG132, prevents all manifestations of thymocyte apoptosis induced by the glucocorticoid receptor agonist dexamethasone or by the topoisomerase II inhibitor etoposide. Lactacystin and MG132 prevent the early disruption of the mitochondrial transmembrane potential (delta psi(m)), which precedes caspase activation, exposure of phosphatidylserine, and nuclear DNA fragmentation. In contrast, stabilization of the delta psi(m) using the permeability transition pore inhibitor bongkrekic acid or inhibition of caspases by N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone does not prevent the activation of proteasomes, as determined with the fluorogenic substrate N-succinyl-L-leucyl-L-leucyl-L-valyl-L-tyrosine-7-amido-4-methylcoumarin . Thus, proteasome activation occurs upstream from mitochondrial changes and caspase activation. Whereas the proteasome-specific agents lactacystin and MG132 truly maintain thymocyte viability, a number of protease inhibitors that inhibit nuclear DNA fragmentation (acetyl-Asp-Glu-Val-Asp-fluoromethylketone; N-Boc-Asp(OMe)-fluoromethylketone; N-tosyl-L-Phe-chloromethylketone) do not prevent the cytolysis induced by DEX or etoposide. These latter agents fail to interfere with the preapoptotic delta psi(m) disruption. Altogether, our data indicate that different proteases may be involved in the pre- or postmitochondrial phase of apoptosis. Only those protease inhibitors that interrupt the apoptotic process at the premitochondrial stage can actually preserve cell viability.
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PMID:Proteasome activation occurs at an early, premitochondrial step of thymocyte apoptosis. 964 4

Previous work in our laboratory has shown that acute exposure of primary rat hepatocyte cultures to non-toxic concentrations of arsenite causes major decreases in the DEX-mediated induction of CYP3A23 protein, with minor decreases in CYP3A23 mRNA. To elucidate the mechanism for these effects of arsenite, the effects of arsenite and proteasome inhibition, separately and in combination, on induction of CYP3A23 protein were compared. The proteasome inhibitor, MG132, inhibited proteasome activity, but also decreased CYP3A23 mRNA and protein. Lactacystin, another proteasome inhibitor, decreased CYP3A23 protein without affecting CYP3A23 mRNA at a concentration that effectively inhibited proteasome activity. This result, suggesting that the action of lactacystin is similar to arsenite and was post-transcriptional, was confirmed by the finding that lactacystin decreased association of DEX-induced CYP3A23 mRNA with polyribosomes. Both MG132 and lactacystin inhibited total protein synthesis, but did not affect MTT reduction. Arsenite had no effect on ubiquitination of proteins, nor did arsenite significantly affect proteasomal activity. These results suggest that arsenite and lactacystin act by similar mechanisms to inhibit translation of CYP3A23.
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PMID:Effect of proteasome inhibition on toxicity and CYP3A23 induction in cultured rat hepatocytes: comparison with arsenite. 1708 55

Cellular stress or injury can result in mitochondrial dysfunction, which has been linked to many chronic neurological disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Stressed and dysfunctional mitochondria exhibit an increase in large conductance mitochondrial membrane currents and a decrease in bioenergetic efficiency. Inefficient energy production puts cells, and particularly neurons, at risk of death when energy demands exceed cellular energy production. Here we show that the candidate ALS drug dexpramipexole (DEX; KNS-760704; ((6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) and cyclosporine A (CSA) inhibited increases in ion conductance in whole rat brain-derived mitochondria induced by calcium or treatment with a proteasome inhibitor, although only CSA inhibited calcium-induced permeability transition in liver-derived mitochondria. In several cell lines, including cortical neurons in culture, DEX significantly decreased oxygen consumption while maintaining or increasing production of adenosine triphosphate (ATP). DEX also normalized the metabolic profile of injured cells and was protective against the cytotoxic effects of proteasome inhibition. These data indicate that DEX increases the efficiency of oxidative phosphorylation, possibly by inhibition of a CSA-sensitive mitochondrial conductance.
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PMID:Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetic efficiency. 2236 37

The introduction of proteasome inhibitors (PIs), such as bortezomib (BTZ), and immunomodulatory drugs (IMiDs), including thalidomide (THAL) and lenalidomide (LEN), as first-line therapies in multiple myeloma (MM) has markedly improved the clinical outcomes of patients. However, MM remains incurable, and most patients eventually relapse. Moreover, prognosis is poor in patients who exhibit resistance to BTZ or LEN, and novel therapeutic approaches for such patients are urgently needed. Currently, the following six drugs are available for use in relapsed patients: second generation PIs (carfilzomib and ixazomib), an IMiD (pomalidomide), a histone deacetylase (HDAC) inhibitor (panobinostat), and two monoclonal antibodies (elotuzumab and daratumumab). The choice of treatment should be individualized based on certain factors, such as age, presence of comorbidities, frailty, cytogenetic risk, efficacy and toxicity of prior treatments, and the duration of the previous response. A course of triplet therapy containing two novel agents along with DEX is recommended, on first relapse, in fit and healthy patients, whereas doublet therapy is preferred for unfit or frail patients. Retreatment of relapsed/refractory MM (RRMM) with monoclonal antibodies and IMiDs is promising because these drugs have immunostimulatory effects. In addition, novel agents, including an anti-BCMA antibody-drug conjugate, are being studied. Clinical trials are needed to define the optimal treatment strategy for RRMM.
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PMID:[Management of multiple myeloma in the relapsed/refractory patient]. 3159 51