A proteasomal stress response: pre‐treatment with proteasome inhibitors increases proteasome activity and reduces neuronal vulnerability to oxidative injury

Abstract

We report here that exposure to low concentrations of proteasome inhibitors (e.g. 10-100 nM MG-132, 0.1-3 nM epoxomicin or 10-30 nM clasto-lactacystin b-lactone) resulted in an enhancement, rather than an inhibition, of proteasome activity in cultured neocortical neurons. Size-fractionation chromatography confirmed that the enhanced peptide cleavage activity was associated with proteasome-sized complexes. This sub toxic exposure reduced neuronal death caused by subsequent exposure to oxidative stress (100-200 lM H 2 O 2 for 30 min, 24-h exposure to 100 lM paraquat or 7.5 lM menadione), but did not alter vulnerability to excitotoxicity (5-min exposure to 30-100 lM NMDA or 24 exposure to 12 lM NMDA). Sub toxic proteasome inhibitor exposure caused an increase in levels of proteasome core subunit proteins and mRNAs, but not in levels of potentially cytoprotective heat shock proteins (hsp70, hsp90 and hsp40). The neuroprotective effects of proteasome inhibitor pre-treatment were blocked by coapplication of proteasome inhibitors during the oxidative insult. These findings support a model in which sublethal proteasome inhibition induces neurons to increase proteasome activity and promotes resistance to oxidative injury and suggests that enhancement of proteasome activity is a potential therapeutic target for diseases in which oxidative stress has been implicated.

Gα12/13 Basally Regulates p53 through Mdm4 Expression

“…The weak intensities at 12 to 24 h after MG132 treatment might be associated with its biphasic effects (i.e., increase in proteasomal activity because of low concentrations of MG132; ref. 33). Similar time courses in p53 accumulation were observed in those treated with lactacystin ( Fig.…”

Chronic Proteasome Inhibition Contributes to Coronary Atherosclerosis

“…Culture-based studies confirm these findings by demonstrating that higher yet nontoxic degrees of proteasome inhibition increase endogenous oxidative stress and render cells more susceptible to oxidative stress-related injury. 13,33,34 Taken together, the current results extend in vitro findings on the interaction between oxidative stress and proteasome activity. Coronary proteasome activity is increased in hypercholesterolemia in association with enhanced oxidative stress, and oxidative stress is increased by chronic in vivo proteasome inhibition.…”

Dermcidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues

“…Alternatively, expression might protect cells from oxidative stress by induction of the proteasome system, which is known to be activated by glycosylated PIF (Smith and Tisdale, 2003;Whitehouse and Tisdale, 2003). Proteasome induction has been associated with improved survival of both neuronal cells and liver cells following oxidative stress (Donohue Jr et al, 2004;Lee et al, 2004). Finally, the fact that double mutation of N32 and N44 contrasted with single N32 mutation in abrogating the survival effect on MTT assay suggests that a mitochondrial pathway may also be involved.…”