title: Evidence for anti-apoptotic roles of proteasome activator 28γ via inhibiting caspase activity.
abstract: Proteasome activator PA28γ (REGγ, Ki antigen) has recently been demonstrated to display anti-apoptotic properties via enhancing Mdm2-p53 interaction, thereby facilitating ubiquitination and down-regulation of the tumor suppressor p53. In this study we demonstrate a correlation between cellular PA28γ levels and the sensitivity of cells towards apoptosis in different cellular contexts thereby confirming a role of proteasome activator PA28γ as an anti-apoptotic regulator. We investigated the anti-apoptotic role of PA28γ upon UV-C stimulation in B8 mouse fibroblasts stably overexpressing the PA28γ-encoding PSME3 gene and upon butyrate-induced apoptosis in human HT29 adenocarcinoma cells with silenced PSME3 gene. Interestingly, our results demonstrate that PA28γ has a strong influence on different apoptotic hallmarks, especially p53 phosphorylation and caspase activation. In detail, PA28γ and effector caspases mutually restrict each other. PA28γ is a caspase substrate, if PA28γ levels are low. In contrast, PA28γ overexpression reduces caspase activities, including the caspase-dependent processing of PA28γ. Furthermore, overexpression of PA28γ resulted in a nuclear accumulation of transcriptional active p53. In summary, our findings indicate that even in a p53-dominated cellular context, pro-apoptotic signaling might be overcome by PA28γ-mediated caspase inhibition.
authors.affiliation: Department of Biochemistry, Faculty of Natural Sciences, Brandenburg Technical University Cottbus-Senftenberg (BTU C-S), Großenhainer Str. 57, 01968, Senftenberg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Moncsek
authors.forename: Melanie
authors.initials: M
authors.lastname: Gruner
authors.forename: Hannes
authors.initials: H
authors.lastname: Meyer
authors.forename: Andrea
authors.initials: A
authors.lastname: Lehmann
authors.forename: Peter-Michael
authors.initials: PM
authors.lastname: Kloetzel
authors.forename: Ralf
authors.initials: R
authors.lastname: Stohwasser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001324:Autoantigens / Q000378:metabolism*; D002087:Butyrates / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000528:radiation effects; D019073:HT29 Cells / Q000528:radiation effects; D006801:Humans; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D002087:Butyrates; D004791:Enzyme Inhibitors; C099558:Ki antigen; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D045304:Cytochromes c; D020169:Caspases; D046988:Proteasome Endopeptidase Complex