Activation of CPP32-like Proteases Is Not Sufficient to Trigger Apoptosis: Inhibition of Apoptosis by Agents that Suppress Activation of AP24, but Not CPP32-like Activity

Wright, Susan C.; Schellenberger, Ute; Wang, Hong; Kinder, David H.; Talhouk, Jamil W.; Larrick, James W.

doi:10.1084/jem.186.7.1107

Cited by 75 publications

(50 citation statements)

References 49 publications

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“…Nonetheless, transfection of p23 did not induce apoptosis in SaOS-2 cells, which is also consistent with the results obtained in 7TD1 cells where p23 induction occurs in the absence of apoptosis. Since p23 results from the cleavage of p27 by a CPP32-like caspase our results support the hypothesis already suggested by others (Miossec et al, 1997;Singer et al, 1995;Wright et al, 1997) that caspases can be activated in the course of physiological functions unrelated to apoptosis. The fact that the cleavage of p27 occurred speci®cally in G 1 phase suggests that these proteases could be regulated during the progression through the cycle.…”

Section: Discussionsupporting

confidence: 91%

Evidence for a p23 caspase-cleaved form of p27[KIP1] involved in G1 growth arrest

et al. 1999

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p27 [KIP1] (p27) is a cyclin dependent kinase inhibitor, involved in the negative regulation of G 1 progression in response to a number of anti-proliferative signals. In this study we show, in growing mouse hybridoma (7TD1) and human myeloma (U266) cell lines, that p27 is highly expressed but slightly upregulated when cells are arrested, regardless to the phases of the cell cycle. In contrast, the speci®c blockade of these cells in early G 1 phase reveals the induction of a protein of 23 kDa (p23) speci®cally recognized by polyclonal anti-p27 antibodies raised against the NH2 terminal part of p27 but not by anti-p21 [CIP1] antibodies. Experiments using caspase inhibitors strongly suggest that p23 results from the proteolysis of p27 by a`caspase-3-like' protease. This cleavage leads to the cytosolic sequestration of p23 but does not alter its binding properties to CDK2 and CDK4 kinases. Indeed, p23 associated in vivo with high molecular weight complexes and coprecipitated with CDK2 and CDK4. We demonstrate by transfection experiments in SaOS-2 cells that p23 induces a G 1 phase growth arrest by inhibition of cyclin/CDK2 activity. In summary we describe here a caspase-cleaved form of p27, induced in absence of detectable apoptosis and likely involved in cell cycle regulation.

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Section: Discussionsupporting

confidence: 91%

Evidence for a p23 caspase-cleaved form of p27[KIP1] involved in G1 growth arrest

et al. 1999

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“…For example, serine proteases have been reported to play a crucial role in the early cleavage of chromatin into 50 -300 kb pieces before they are digested to nucleosome-sized fragments by caspase activated DNAse (CAD), also termed DNA fragmentation factor (DFF) (Hughes et al, 1997). Similarly, another serine protease, AP24, becomes activated during apoptosis, and agents that inhibit activation of this protease protect cells from tumor necrosis factor-a (TNF-a) and UV-induced apoptosis (Wright et al, 1997). Interestingly, caspase activation by non-caspase proteinases also represents another mechanism of activation (Liu et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

Gordon

Rastegar

et al. 2002

Oncogene

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We report here that expression of proteinase 3 (PR3), a serine protease, is down-regulated in the HL60/ADR multidrug resistant variant of the human myelogenous leukemia cell line HL-60, and that down-regulation of PR3 is associated with doxorubicin (DOX) resistance in these cells. To determine whether PR3 is involved in DOX-induced apoptosis in HL-60 cells, and whether its loss causes resistance to DOX, we inhibited PR3 expression by an anti-sense PR3 oligodeoxynucleotide and showed that inhibition of PR3 expression results in a significant reduction in DOX-induced DNA fragmentation and increased resistance to DOX-induced apoptosis. Our results revealed that PR3-mediated DOX-induced apoptosis in HL-60 cells is independent of the loss of mitochondrial membrane potential (DC m ) and activation of the caspase-8 and -9 pathways. Moreover, while PR3 is involved in the cleavage of caspase-3, PR3-mediated DOX-induced DNA fragmentation and apoptosis were not prevented by a specific inhibitor of caspase-3. These data suggest that activation of caspase-3 alone is not sufficient to trigger PR3-mediated DOX-induced apoptosis. Treatment with an anti-PR3 oligomer significantly decreased reactive oxygen species (ROS) generation in cells treated with low concentrations of DOX, revealing a role for PR3 in enhancing production of DOX-induced ROS. Moreover, DOX-induced apoptosis at 0.001 -0.01 mM was only inhibited in HL-60 cells pre-treated with the antioxidant N-acetyl-cysteine in the absence of anti-PR3, revealing that DOX-induced apoptosis in these cells is PR3-and ROS-dependent. Our results show that PR3 is involved in DOX-induced ROS-dependent apoptosis and that its loss is associated with resistance to DOX in HL-60 cells.

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“…It is interesting that the death processes used by c-Myc or Bin1 are each susceptible to inhibition at some level by AEBSF, a serine protease inhibitor which does not generally a ect apoptosis (Kagaya et al, 1997). Serine death proteases and caspases appear to act in various cells in di erent but integrated hierarchies (Kagaya et al, 1997;Wright et al, 1997), so the fact caspases are di erentially activated by c-Myc and Bin1 supports the notion of more than one death signal emerging from cMyc. Results from our laboratory using dominant Figure 9 Implication of a serine protease(s) in programmed cell death by Bin1.…”

Section: Independence From Mitochondrial Processes and Caspasesmentioning

confidence: 98%

The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program

et al. 2000

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Cell death processes are progressively inactivated during malignant development, in part by loss of tumor suppressors that can promote cell death. The Bin1 gene encodes a nucleocytosolic adaptor protein with tumor suppressor properties, initially identi®ed through its ability to interact with and inhibit malignant transformation by c-Myc and other oncogenes. Bin1 is frequently missing or functionally inactivated in breast and prostate cancers and in melanoma. In this study, we show that Bin1 engages a caspase-independent cell death process similar to type II apoptosis, characterized by cell shrinkage, substratum detachment, vacuolated cytoplasm, and DNA degradation. Cell death induction was relieved by mutation of the BAR domain, a putative e ector domain, or by a missplicing event that occurs in melanoma and inactivates suppressor activity. Cells in all phases of the cell cycle were susceptible to death and p53 and Rb were dispensable. Notably, Bin1 did not activate caspases and the broad spectrum caspase inhibitor ZVAD.fmk did not block cell death. Consistent with the lack of caspase involvement, dying cells lacked nucleosomal DNA cleavage and nuclear lamina degradation. Moreover, neither Bcl-2 or dominant inhibition of the Fas pathway had any e ect. In previous work, we showed that Bin1 could not suppress cell transformation by SV40 large T antigen. Consistent with this ®nding, we observed that T antigen suppressed the death program engaged by Bin1. This observation was interesting in light of emerging evidence that T antigen has roles in cell immortalization and human cell transformation beyond Rb and p53 inactivation. In support of a link to c-Mycinduced death processes, AEBSF, a serine protease inhibitor that inhibits apoptosis by c-Myc, potently suppressed DNA degradation by Bin1. Our ®ndings suggest that the tumor suppressor activity of Bin1 re¯ects engagement of a unique cell death program. We propose that loss of Bin1 may promote malignancy by blunting death penalties associated with oncogene activation. Oncogene (2000) 19, 4669 ± 4684.

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Activation of CPP32-like Proteases Is Not Sufficient to Trigger Apoptosis: Inhibition of Apoptosis by Agents that Suppress Activation of AP24, but Not CPP32-like Activity

Cited by 75 publications

References 49 publications

Evidence for a p23 caspase-cleaved form of p27[KIP1] involved in G1 growth arrest

Evidence for a p23 caspase-cleaved form of p27[KIP1] involved in G1 growth arrest

Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant

The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program

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