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decreased active effector caspase levels. Consistently and vice versa, PMSE3 miRNA-mediated PA28γ downregulation was accompanied by increased sensitivity to butyrate-triggered apoptosis of HT-29 cells and increased levels of active caspase-3/caspase-7 [46]. Reduced caspase

The anti-apoptotic impact of high PA28γ levels could not solely be explained by enhanced PA28γ-mediated degradation of pro-apoptotic p53 as suggested by others [66]. Our current findings support a model (Figure 2A and E), where high PA28γ levels inhibit effector caspase-3/caspase-7, while at low PA28γ levels, caspase-3/caspase-7 activity and PA28γ turnover are increased. As a reasonable explanation, the high level of PA28γ favors heptamer stability, whereas at low concentrations, monomeric PA28γ may be more susceptible to cleavage by activated effector caspases [46, 47]. Furthermore, we found that proteasome inhibition stabilized active caspase-3 levels, indicating that the PA28γ-dependent degradation of caspase-3/ caspase-7 is indeed proteasome-dependent [46]. Since the RING domain of IAP proteins ubiquitinates caspase-3/caspase-7 [95], the canonical UPS is certainly involved in regulating effector caspase activity. If PA28γ conducts restriction of caspase-3/caspase-7 activity through enhancement of physical interaction between IAPs and caspases, or directly via the PA28γ-20S

In light of the fact that the apoptotic potential of the cell is finally restricted by caspase levels and their execution efficiencies [96], the importance of check and balance for controlling caspase activity appears to be obvious. Recently, the impact of posttranslational modification on activity and stability of caspase-3 has been reviewed [97]. Apart from inhibitory and stimulatory phosphorylation, ubiquitination plays an important yet not a fully understood role. However, cIAP1-dependent ubiquitination of a processing intermediate of caspase-3 was followed by proteasome-dependent degradation of caspase-3. Interestingly, proteasome inhibitors stabilizing majorly active caspase-3 among other effector caspases enhanced apoptosis [97]. The integration of the recent knowledge on proteasomal contribution to regulation of apoptosis via UIPP and UPS might lead to a refined concept in system biology of apoptosis [98]. Despite of the remaining questions, experimental evidences indicate that tumor survival and resistance to therapeutic approaches may crucially relate to a plethora of new roles of PA28γ in

the regulation of apoptosis, autophagy, inflammation, and metabolic adaptation.

This work has been supported by grants from the Ministry for Science, Research and Culture, MWFK, Brandenburg, via BTU Cottbus-Senftenberg (project no. c90110631) and via Health Campus Brandenburg, Cluster "Consequences of age-associated cell and organ function"

activities were not due to transcriptional but posttranslational regulation.

proteasome UIPP route, has to be clarified in the future.

84 Current Understanding of Apoptosis - Programmed Cell Death

4. Concluding remarks

Acknowledgements

(project no. 92106360).

Ralf Stohwasser

Address all correspondence to: ralf.stohwasser@b-tu.de

Brandenburg Technical University Cottbus-Senftenberg, Senftenberg, Germany
