Type

Journal Article

Authors

Markus Rehm
Heinrich J Huber
Jochen H M Prehn
Lorna Flanagan
Bartlomiej Tomiczek
Christian T Hellwig
Egle Passante
Maike A Laussmann

Subjects

Biochemistry

Topics
epoxomicin tnf related apoptosis inducing ligand proteasome inhibitors casp8 protein human hela cells enzyme activation antineoplastic agents boronic acids pyrazines apoptosis proteasome endopeptidase complex genetics metabolism signal transduction protease inhibitors bortezomib drug effects pharmacology caspase 8 oligopeptides humans tnfsf10 protein human

Proteasome inhibition can impair caspase-8 activation upon submaximal stimulation of apoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) signaling. (2012)

Abstract Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) can induce extrinsic apoptosis, resulting in caspase-8 activation, but may also initiate transcription-dependent prosurvival signaling. Proteasome inhibitors were suggested to promote TRAIL signal transduction through the death-inducing signaling complex (DISC) by modulating the relative abundance of core DISC components, thereby enhancing caspase-8 activation and apoptosis. To test this hypothesis, we quantified the changes in DISC protein levels as an early consequence of proteasome inhibition in HeLa cervical cancer cells and, based on these data, mathematically modeled the proapoptotic TRAIL signaling toward caspase-8 activation. Modeling results surprisingly suggested that caspase-8 activation might be delayed in presence of proteasome inhibitors, in particular at submaximal TRAIL doses. Subsequent FRET-based single cell time-lapse imaging at conditions where transcription dependent prosurvival signaling was blocked confirmed this hypothesis: caspase-8 activity was delayed by hours in the presence of proteasome inhibitors epoxomicin or bortezomib. Corresponding delays were detected for effector caspase processing and cell death. Contrary to current models, we therefore provide evidence that synergies between TRAIL and proteasome inhibitors do not result from changes in the levels of core DISC signaling proteins.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Markus Rehm, Heinrich J Huber, Jochen H M Prehn, Lorna Flanagan, Bartlomiej Tomiczek, Christian T Hellwig, Egle Passante, Maike A Laussmann

Experts in our system

1
Markus Rehm
Royal College of Surgeons in Ireland
Total Publications: 55
 
2
Heinrich J Huber
Royal College of Surgeons in Ireland
Total Publications: 39
 
3
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
4
Lorna Flanagan
Royal College of Surgeons in Ireland
Total Publications: 23
 
5
Christian T Hellwig
Royal College of Surgeons in Ireland
Total Publications: 11
 
6
E Passante
Royal College of Surgeons in Ireland
Total Publications: 6