Proteolytic Activities That Mediate Apoptosis

Abstract

Since the discovery that cells can activate their own suicide program, investigators have attempted to determine whether the events that are associated with this form of cell death are genetically determined. The discovery that the ced-3 gene of Caenorhabditis elegans encodes a cysteine protease essential for developmentally regulated apoptosis ignited interest in this area of research. As a result, we now know that cell death is specified by a number of genes and that this biologic process contributes significantly to development, tumorigenesis, and autoimmune disease. In this review I summarize what is currently known about signaling pathways involved in apoptosis, with particular emphasis on the function of the cysteine proteases known as caspases. However, there is also evidence that protease-independent cell death pathways exist. Is there a relationship between these two distinct mechanisms? If so, how do they communicate? Finally, even though the involvement of tumor necrosis factor/nerve growth factor family of receptors and cysteine proteases has been elegantly established as a component of many apoptotic signaling pathways, what happens downstream of these initial events? Why are only a selected group of cellular proteins-many nuclear-the targets of these proteases? Are nuclear events essential for apoptosis in vivo? Are the cellular genes that encode products involved in apoptotic signaling frequent targets of mutation/alteration during tumorigenesis? These are only a few questions that may be answered in the next ten years.

Enhanced Expression of Caspase-3 in Hypertrophic Scars and Keloid: Induction of Caspase-3 and Apoptosis in Keloid Fibroblasts In Vitro

“…Previous studies have indicated that DEVD has specificity for caspase-3 due to its similarities to the cleavage site of the caspase-3 substrate, PARP (Fadeel et al, 1998;Gu et al, 1995;Hasegawa et al, 1996;Izban et al, 1999;Kidd, 1998;Nicholson et al, 1995;Thornberry et al, 1997). In the present study, we have shown that the addition of DEVD-FMK after serum deprivation significantly decreases apoptosis of KFB-2, thereby confirming that caspase-3 plays an important role in serum deprivation-induced apoptosis in KFB cells.…”

Oxidative stress induces caspase-independent retinal apoptosis in vitro

“…This study describes a retinal cell apoptosis pathway in vitro which does not involve caspase activity. The lack of caspase activity as these cells die is evidenced by the lack of caspase-3 activation (Figure 2), the absence of PARP cleavage (data not shown) ± a substitute for several members of the caspase family 49 ± as well as the failure of several, broad spectrum caspase inhibitors to prevent or alter the characteristics and kinetics of the cell death observed (Figure 2 and data not shown). The retinal cell death described in this study retains key characteristics of apoptotic cell death in the absence of caspase activity.…”

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

“…However the e ects of the inhibitors Z-VAD.FMK and Z-DEVD.FMK are not su cient to indicate which caspase activity is responsible, or indeed to establish that these enzymes are the actual catalysts of eIF4G cleavage. Both Z-VAD.FMK and Z-DEVD.FMK have relatively broad speci®cities against a number of caspases (Kidd, 1998). ZnCl 2 is an inhibitor of caspase-3 but it is not clear whether it is also active against other caspases (Perry et al, 1997).…”