Role of proteases in activation of apoptosis

Sukharev, S.A; Pleshakova, O.V; Садовников, В. Б.

doi:10.1038/sj.cdd.4400263

Cited by 29 publications

(17 citation statements)

References 31 publications

(33 reference statements)

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“…7). Recently, TPCK has been shown to to block the conversion of the inactive 32-kDa caspase-3 precursor into the mature caspase-3 (35), thus providing an explanation of its inhibitory effect on apopotosis reported in several studies (11). It is noteworthy that, under our conditions, no increase in a chymotrypsin activity was observed (Fig.…”

Section: Discussionmentioning

confidence: 44%

Induction of a Caspase-3-like Activity by Calcium in Normal Cytosolic Extracts Triggers Nuclear Apoptosis in a Cell-free System

Juin¹,

Pelletier

Oliver

et al. 1998

Journal of Biological Chemistry

111

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Calcium is involved in several steps of the apoptotic process. In nuclei, endonucleases are presumed to be the main targets of calcium; however, little is known about its role during the cytosolic phase of apoptosis. We used a cell-free system to address this question. Our results show that CaCl 2 triggered nuclear apoptosis (i.e. typical morphological change and DNA fragmentation) at concentrations of 5 mM. This concentration was lowered 10-fold by the co-incubation with cytosolic extracts from nonapoptotic cells. Apoptotic changes induced by the incubation of nuclei with CaCl 2 in the presence of these cytosols were strongly reduced in the presence of an inhibitor of caspase-3 and to a lesser extent by an inhibitor of caspase-1. We also show that calcium-induced apoptosis is affected by protease inhibitors such as N-tosyl-L-phenylalanine chloromethyl ketone, but not by calpain or several lysosomal protease inhibitors. The addition of CaCl 2 to the cell-free system increased a caspase-3 activity in nonapoptotic cytosols as shown by specific antibodies and an enzymatic assay. No activation of a caspase-3-like activity by the addition of cytochrome c was observed in these extracts under similar conditions. The enhanced caspase-3 activity induced by calcium was inhibited by protease inhibitors affecting morphological nuclear apoptosis except for those responsible for the degradation of lamin A. These results suggest that CaCl 2 could trigger, in normal cells, an apoptotic cascade through the activation of cytosolic caspase-3 activity.

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Section: Discussionmentioning

confidence: 44%

Induction of a Caspase-3-like Activity by Calcium in Normal Cytosolic Extracts Triggers Nuclear Apoptosis in a Cell-free System

Juin¹,

Pelletier

Oliver

et al. 1998

Journal of Biological Chemistry

111

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“…4 Whether the caspase cascade and the lysosomal proteolytic pathway intersect during onset of apoptosis is not known. We therefore looked for the involvement of caspases in the apoptotic pathway initiated by CB and CD inhibitors.…”

Section: Apoptosis By Cathepsin Inhibitors Is Caspase-dependentmentioning

confidence: 99%

“…With few exceptions, the caspase system seems to be the most universally involved one. 3,4 Recently, proteases resident within the endosomal-lysosomal compartment (cathepsins) have also been associated with apoptosis. [5][6][7][8][9] These studies demonstrated the need for a cathepsin-mediated proteolytic event in the apoptotic pathway triggered by cytokines or antiblastic drugs.…”

mentioning

confidence: 99%

Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Castino¹,

Pace²,

Démoz³

et al. 2001

Intl Journal of Cancer

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Neuroblastoma is the most common type of cancer in infants. In children this tumor is particularly aggressive; despite various new therapeutic approaches, it is associated with poor prognosis. Given the importance of endosomallysosomal proteolysis in cellular metabolism, we hypothesized that inhibition of lysosomal protease would impact negatively on neuroblastoma cell survival. Treatment with E-64 or CA074Me (2 specific inhibitors of cathepsin B) or with pepstatin A (a specific inhibitor of cathepsin D) was cytotoxic for 2 neuroblastoma cell lines having different degrees of malignancy. Cell death was associated with condensation and fragmentation of chromatin and externalization of plasma membrane phosphatidylserine, 2 hallmarks of apoptosis. Concomitant inhibition of the caspase cascade protected neuroblastoma cells from cathepsin inhibitor-induced cytotoxicity. These data indicate that prolonged inhibition of the lysosomal proteolytic pathway is incompatible with cell survival, leading to apoptosis of neuroblastoma cells, and that the cathepsin-mediated and caspase-mediated proteolytic systems are connected and cooperate in the regulation of such an event. Since modern antitumor chemotherapy is aimed at restoring the normal rate of apoptosis in neoplastic tissues, the demonstration that endosomal-lysosomal cathepsins are involved in this process may constitute a basis for novel strategies that include cathepsin inhibitors in the therapeutic regimen. © 2002 Wiley-Liss, Inc. Key words: apoptosis; neuroblastoma; caspases; cathepsins; protease inhibitorsAltered regulation of cell survival and death, including apoptosis, is considered an important factor in tumor development and progression, as well as in the response to antineoplastic therapy. 1,2 The molecular pathways controlling apoptosis include a complex network of intracellular proteases that act in an orderly sequence on cellular substrates and lead to characteristic modifications of cell morphology with eventual DNA cleavage and apoptotic body formation. Several proteolytic systems have been shown to participate in the apoptotic process, depending on the cell type and stimuli adopted. With few exceptions, the caspase system seems to be the most universally involved one. 3,4 Recently, proteases resident within the endosomal-lysosomal compartment (cathepsins) have also been associated with apoptosis. 5-9 These studies demonstrated the need for a cathepsin-mediated proteolytic event in the apoptotic pathway triggered by cytokines or antiblastic drugs. In addition, the active participation of the autophagic proteolytic pathway, particularly of lysosomal cathepsins B and D (CB, CD), has been envisaged in rat pheochromocytoma PC12 cell death after nutrient and serum factor deprivation. In this model of caspasedependent apoptosis, CD acted as a death factor, whereas CB acted as a pro-survival factor. 10 We followed an opposite approach, assuming that the endosomal-lysosomal proteolytic pathway serves crucial functions for cell viability. Indeed, experiments usi...

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“…These caspases have been shown to be intracellular and are directly involved in the intracellular events that occur as the cell undergoes apoptosis. Other proteases apart from the caspases have been shown to be activated during apoptosis, including calpains [Squier and Cohen, 1996] and serine proteases [Sukharev et al, 1997].…”

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confidence: 99%

Increased ecto-metallopeptidase activity in cells undergoing apoptosis

et al. 2000

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Release from the cell surface of a variety of growth factors, cytokines, and proteases follows exposure to genetically stressful agents capable of inducing apoptosis and necrosis. Increased ectoprotease activity is responsible for their release. We show that increased activity of several metalloproteases on the HeLa cell surface occurs after stresses due to UVC, actinomycin D, cycloheximide, and cisplatinum, which induce the release of transforming growth factor-alpha (TGFalpha) and other bioactive molecules. The ectoprotease activities increase preferentially on apoptotic cells, while little change occurs in viable cells. Gross decreases, except for the putative TGFalphaase activity, accompany necrosis. These changes may contribute to tissue repair and the absence of an inflammatory reaction to apoptotic cell death. They appear to be due to preferential enzyme activation or to retention by cells undergoing significant categorical decreases in protein content.

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Role of proteases in activation of apoptosis

Cited by 29 publications

References 31 publications

Induction of a Caspase-3-like Activity by Calcium in Normal Cytosolic Extracts Triggers Nuclear Apoptosis in a Cell-free System

Induction of a Caspase-3-like Activity by Calcium in Normal Cytosolic Extracts Triggers Nuclear Apoptosis in a Cell-free System

Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Increased ecto-metallopeptidase activity in cells undergoing apoptosis

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