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Programmed cell death and the proteasome
1Max Planck Institut für Physiologische und Klinische Forschung, Parkstr. 1, 61231 Bad Nauheim Germany. hdrexler@kerckhoff.mpg.de
Abstract:
A characteristic feature of apoptotic cell death is the activation of a cascade of cytoplasmic proteases that results in the cleavage of a limited number of target proteins. A central role in these proteolytic events has been assigned to members of the capase family. However, the use of low molecular weight proteasomal inhibitors has also demonstrated that protein degradation or processing by the ubiquitin-proteasome system of the cell has a decisive impact on cell survival and death as well, depending on the cell type and/or the proliferative status of the cells studied. Treatment of proliferating cells with proteasome inhibitors leads to cell death, potentially involving an internal signalling conflict between accumulating levels of the cdk inhibitor p27Kip1 and c-myc. In contrast, in terminally differentiated cells the same compounds have the opposite effect of blocking apoptosis, possibly by preventing proteasome-mediated degradation of a capase inhibitor. In this review the role of proteasome-mediated proteolysis in the dying cell is discussed and apparently conflicting results are integrated into a working hypothesis which functionally locates the proteasome upstream of capase3-like enzymes.
Insights
The ubiquitin-proteasome system impacts cell death, with proteasome inhibitors causing death in proliferating cells but blocking apoptosis in differentiated cells. This suggests the proteasome acts upstream of caspase enzymes.
Area of Science:
- Cellular Biology
- Biochemistry
Background:
- Apoptotic cell death involves protease cascades, notably caspases.
- The ubiquitin-proteasome system also influences cell survival and death.
- Proteasome activity's role in apoptosis appears context-dependent.
Purpose of the Study:
- To review the role of proteasome-mediated proteolysis in cell death.
- To integrate conflicting findings on proteasome inhibitors and apoptosis.
- To propose a model for the proteasome's function in the apoptotic pathway.
Main Methods:
- Literature review of studies on proteasome inhibitors and apoptosis.
- Analysis of cell type and proliferative status in response to proteasome inhibition.
- Integration of data to formulate a working hypothesis.
Main Results:
- Proteasome inhibitors induce cell death in proliferating cells, potentially via p27Kip1 and c-myc accumulation.
- In terminally differentiated cells, proteasome inhibitors block apoptosis, possibly by stabilizing caspase inhibitors.
- Conflicting results suggest a complex regulatory role for the proteasome.
Conclusions:
- The proteasome plays a critical role in regulating cell death pathways.
- The proteasome likely functions upstream of caspase-3-like enzymes in apoptosis.
- Cellular context (proliferative status) dictates the proteasome's effect on apoptosis.