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Apoptosis and the proteasome.

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Program in Molecular and Cellular Biology, University of Massachusetts, Amherst 01003, USA.


The ubiquitin-proteasome pathway is responsible for the regular turnover of a wide variety of proteins and is a critical regulator of many cellular processes. Although this pathway is abundant and ubiquitous, it is also discriminating. This specificity is achieved because there are multiple levels of regulation at work in the pathway. X-ray crystallographic data on the eukaryotic 20S proteasome suggest that substantial rearrangement of the alpha rings, probably mediated by the association of additional regulatory complexes, is required to allow access of substrates into the inner core of the complex. The associated complexes also confer a ubiquitin-dependence on the proteasome, requiring that potential substrates be tagged with chains of ubiquitin proteins. The presence of multiple ubiquitinating enzymes that favor distinct substrates provides a way for a cell to regulate what proteins are to be ubiquitinated. In some cases ubiquitination is not required, but we now know that other modifications, such as phosphorylation and protein-protein interactions, are also important for targeting proteins for degradation. Even with the existence of so many regulatory controls, it is difficult to imagine how one complex can perform so many tasks. As more information is gathered about the proteasome, we begin to understand that all proteasomes are not exactly the same. For example, there is strong evidence that proteasomes involved in antigen presentation differ in both composition and function from proteasomes involved in other processes. The past image of the proteasome as a static structure is being shed, and a new image is emerging that portrays the complex as dynamic and flexible, able to tailor its composition and function to meet a particular need. With this new image of the proteasome in mind, investigators are looking at the potential involvement of the proteasome in cell death. Inhibitor studies have demonstrated a requirement for proteasomes during apoptosis in noncycling and differentiated cells. Similar studies in cycling cells suggest that the proteasome may regulate a cell's decision to proliferate, differentiate, or die. It will be necessary in the future to supplement the peptide and lactacystin studies with work that is not inhibitor-driven since the specificity of an inhibitor for a particular protease is always in question. In addition, a real understanding of how proteasomes may regulate this process awaits the identification of its substrates. With cell death investigators showing increased interest in proteasomes, it may be possible in the next few years to determine the precise role of the proteasome in the pathways that lead to the death of a cell.

[Indexed for MEDLINE]

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