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- Title
Imaging 26S proteasome activity and inhibition in living mice.
- Authors
Luker, Gary D; Pica, Christina M; Song, Jiling; Luker, Kathryn E; Piwnica-Worms, David
- Abstract
The ubiquitin-proteasome pathway is the central mediator of regulated proteolysis in cells, and defects in this pathway are associated with cancer and neuro-degenerative diseases. To assess 26S proteasome function in living animals, we developed a ubiquitin-luciferase reporter for bioluminescence imaging. The reporter was degraded rapidly under steady-state conditions and stabilized in a dose- and time-dependent manner in response to proteasome inhibitors. Using bioluminescence imaging after one dose of the chemotherapeutic proteasome inhibitor bortezomib (PS-341), proteasome function in tumor xenografts was blocked within 30 min and returned to nearly baseline by 46 h. After a 2-week regimen of bortezomib, however, imaging of target tumors showed significantly enhanced proteasome inhibition that no longer returned to baseline. The ubiquitin-luciferase reporter enables repetitive tissue-specific analysis of 26S proteasome activity in vivo and should facilitate development and validation of proteasome inhibitors in mouse models, as well as investigations of the ubiquitin-proteasome pathway in disease pathogenesis.
- Subjects
UBIQUITIN; PROTEOLYSIS; MICE physiology
- Publication
Nature Medicine, 2003, Vol 9, Issue 7, p969
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm894