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Protease activation in apoptosis induced by MAL

Köhler, C; Håkansson, Anders P LU ; Svanborg, C LU ; Orrenius, S and Zhivotovsky, B (1999) In Experimental Cell Research 249(2). p.8-260
Abstract

The proteolytic caspase cascade plays a central role in the signaling and execution steps of apoptosis. This study investigated the activation of different caspases in apoptosis induced by MAL (a folding variant of human alpha-lactalbumin) isolated from human milk. Our results show that the caspase-3-like enzymes, and to a lesser extent the caspase-6-like enzymes, were activated in Jurkat and A549 cells exposed to MAL. Activated caspases subsequently cleaved several protein substrates, including PARP, lamin B, and alpha-fodrin. A broad-range caspase inhibitor, zVAD-fmk, blocked the caspase activation, the cleavage of proteins, and DNA fragmentation, indicating an important role for caspase activation in MAL-induced apoptosis. Since an... (More)

The proteolytic caspase cascade plays a central role in the signaling and execution steps of apoptosis. This study investigated the activation of different caspases in apoptosis induced by MAL (a folding variant of human alpha-lactalbumin) isolated from human milk. Our results show that the caspase-3-like enzymes, and to a lesser extent the caspase-6-like enzymes, were activated in Jurkat and A549 cells exposed to MAL. Activated caspases subsequently cleaved several protein substrates, including PARP, lamin B, and alpha-fodrin. A broad-range caspase inhibitor, zVAD-fmk, blocked the caspase activation, the cleavage of proteins, and DNA fragmentation, indicating an important role for caspase activation in MAL-induced apoptosis. Since an antagonistic anti-CD95 receptor antibody, ZB4, did not influence the MAL-induced killing, we conclude that this process does not involve the CD95-mediated pathway. While MAL did not directly activate caspases in the cytosol, it colocalized with mitochondria and induced the release of cytochrome c. Thus, these results demonstrate that caspases are activated and involved in apoptosis induced by MAL and that direct interaction of MAL with mitochondria leads to the release of cytochrome c, suggesting that this release is an important step in the initiation and/or amplification of the caspase cascade in these cells.

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published
subject
keywords
Amino Acid Chloromethyl Ketones, Animals, Apoptosis, Caspase 3, Caspase 6, Caspases, Cell Extracts, Cysteine Proteinase Inhibitors, Cytochrome c Group, Cytoplasm, Endopeptidases, Enzyme Activation, Enzyme Precursors, Extracellular Matrix Proteins, Female, Humans, Jurkat Cells, Lactalbumin, Tumor Cells, Cultured
in
Experimental Cell Research
volume
249
issue
2
pages
9 pages
publisher
Academic Press
external identifiers
  • Scopus:0345061654
ISSN
0014-4827
DOI
10.1006/excr.1999.4472
language
English
LU publication?
yes
id
5b8f99f5-08ae-4701-a87c-1b45581f2ba5
date added to LUP
2016-05-21 11:25:23
date last changed
2016-12-04 04:51:50
@misc{5b8f99f5-08ae-4701-a87c-1b45581f2ba5,
  abstract     = {<p>The proteolytic caspase cascade plays a central role in the signaling and execution steps of apoptosis. This study investigated the activation of different caspases in apoptosis induced by MAL (a folding variant of human alpha-lactalbumin) isolated from human milk. Our results show that the caspase-3-like enzymes, and to a lesser extent the caspase-6-like enzymes, were activated in Jurkat and A549 cells exposed to MAL. Activated caspases subsequently cleaved several protein substrates, including PARP, lamin B, and alpha-fodrin. A broad-range caspase inhibitor, zVAD-fmk, blocked the caspase activation, the cleavage of proteins, and DNA fragmentation, indicating an important role for caspase activation in MAL-induced apoptosis. Since an antagonistic anti-CD95 receptor antibody, ZB4, did not influence the MAL-induced killing, we conclude that this process does not involve the CD95-mediated pathway. While MAL did not directly activate caspases in the cytosol, it colocalized with mitochondria and induced the release of cytochrome c. Thus, these results demonstrate that caspases are activated and involved in apoptosis induced by MAL and that direct interaction of MAL with mitochondria leads to the release of cytochrome c, suggesting that this release is an important step in the initiation and/or amplification of the caspase cascade in these cells.</p>},
  author       = {Köhler, C and Håkansson, Anders P and Svanborg, C and Orrenius, S and Zhivotovsky, B},
  issn         = {0014-4827},
  keyword      = {Amino Acid Chloromethyl Ketones,Animals,Apoptosis,Caspase 3,Caspase 6,Caspases,Cell Extracts,Cysteine Proteinase Inhibitors,Cytochrome c Group,Cytoplasm,Endopeptidases,Enzyme Activation,Enzyme Precursors,Extracellular Matrix Proteins,Female,Humans,Jurkat Cells,Lactalbumin,Tumor Cells, Cultured},
  language     = {eng},
  month        = {06},
  number       = {2},
  pages        = {8--260},
  publisher    = {ARRAY(0x7dd7700)},
  series       = {Experimental Cell Research},
  title        = {Protease activation in apoptosis induced by MAL},
  url          = {http://dx.doi.org/10.1006/excr.1999.4472},
  volume       = {249},
  year         = {1999},
}