Type

Journal Article

Authors

Jochen H M Prehn
Heiko Düssmann
Heinrich J Huber
Markus Rehm

Subjects

Biochemistry

Topics
gene expression hela cells xiap protein human proteasome endopeptidase complex genetics metabolism signal transduction caspase inhibitors cytosol caspase 3 physiology systems analysis diablo protein human proteasome inhibitors enzyme activation apoptosis feedback transfection x linked inhibitor of apoptosis protein intracellular signaling peptides and proteins mitochondrial proteins caspases models biological humans casp3 protein human

Systems analysis of effector caspase activation and its control by X-linked inhibitor of apoptosis protein. (2005)

Abstract Activation of effector caspases is a final step during apoptosis. Single-cell imaging studies have demonstrated that this process may occur as a rapid, all-or-none response, triggering a complete substrate cleavage within 15 min. Based on biochemical data from HeLa cells, we have developed a computational model of apoptosome-dependent caspase activation that was sufficient to remodel the rapid kinetics of effector caspase activation observed in vivo. Sensitivity analyses predicted a critical role for caspase-3-dependent feedback signalling and the X-linked-inhibitor-of-apoptosis-protein (XIAP), but a less prominent role for the XIAP antagonist Smac. Single-cell experiments employing a caspase fluorescence resonance energy transfer substrate verified these model predictions qualitatively and quantitatively. XIAP was predicted to control this all-or-none response, with concentrations as high as 0.15 microM enabling, but concentrations >0.30 microM significantly blocking substrate cleavage. Overexpression of XIAP within these threshold concentrations produced cells showing slow effector caspase activation and submaximal substrate cleavage. Our study supports the hypothesis that high levels of XIAP control caspase activation and substrate cleavage, and may promote apoptosis resistance and sublethal caspase activation in vivo.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

Jochen H M Prehn, Heiko Düssmann, Heinrich J Huber, Markus Rehm

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Heiko Düssmann
Royal College of Surgeons in Ireland
Total Publications: 45
 
3
Heinrich J Huber
Royal College of Surgeons in Ireland
Total Publications: 39
 
4
Markus Rehm
Royal College of Surgeons in Ireland
Total Publications: 55