title: Proteasome inhibition elicits a biphasic effect on neuronal apoptosis via differential regulation of pro-survival and pro-apoptotic transcription factors.
abstract: 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.
authors.affiliation: Pharmacology, University of Colorado Health Science Center at Fitzsimons, Aurora, CO 80045, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Butts
authors.forename: H R
authors.initials: HR
authors.lastname: Hudson
authors.forename: D A
authors.initials: DA
authors.lastname: Linseman
authors.forename: S S
authors.initials: SS
authors.lastname: Le
authors.forename: K R
authors.initials: KR
authors.lastname: Ryan
authors.forename: R J
authors.initials: RJ
authors.lastname: Bouchard
authors.forename: K A
authors.initials: KA
authors.lastname: Heidenreich
mesh_terms: 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*
chemical_list: D061988:Proteasome Inhibitors; D014157:Transcription Factors; D046988:Proteasome Endopeptidase Complex