Proteasome inhibition elicits a biphasic effect on neuronal apoptosis via differential regulation of pro-survival and pro-apoptotic transcription factors.
The role of the proteasome in neuronal apoptosis is poorly understood since both anti- and pro-apoptotic effects result from proteasome inhibition. We studied the effects of proteasome inhibition in cultured rat cerebellar granule neurons. Acute exposure to proteasome inhibitors MG-132 and lactacystin blocked caspase activation induced by removal of depolarizing medium. However, chronic treatment with MG-132 activated caspases in neurons maintained in depolarizing potassium. The biphasic effect of MG-132 was hypothesized to be due to differential degradation of anti- and pro-apoptotic proteins. Accordingly, acute exposure to MG-132 inhibited the hyperphosphorylation, loss of DNA binding, ubiquitination, and degradation of the pro-survival transcription factor MEF2D induced by removal of depolarizing medium. In contrast, chronic exposure to MG-132 increased the expression and phosphorylation of c-Jun, elevated levels of the pro-apoptotic protein Bim, and triggered neuronal apoptosis, even in the presence of depolarizing medium. Thus, proteasome inhibition exerts an acute pro-survival action by stabilizing MEF2 transcription factors. However, chronic proteasome inhibition causes a build-up of phosphorylated c-Jun and Bim, which eventually overwhelms the effects of MEF2 and triggers apoptosis.
Butts
B D
BD
Pharmacology, University of Colorado Health Science Center at Fitzsimons, Aurora, CO 80045, USA.
Hudson
H R
HR
Linseman
D A
DA
Le
S S
SS
Ryan
K R
KR
Bouchard
R J
RJ
Heidenreich
K A
KA
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D002531:Cerebellum / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics*
D061988:Proteasome Inhibitors; D014157:Transcription Factors; D046988:Proteasome Endopeptidase Complex