Two distinct pathways leading to nuclear apoptosis.
Santos A. Susin,Eric Daugas,Luigi Ravagnan,Kumiko Samejima,Naoufal Zamzami,Markus Loeffler,Paola Costantini,Karine F. Ferri,Theano Irinopoulou,Marie-Christine Prévost,Tak W. Mak,Josef M. Penninger,William C. Earnshaw,Guido Kroemer +13 more
TLDR
Two redundant parallel pathways may lead to chromatin processing during apoptosis, including one which involves Apaf-1 and caspases, as well as CAD, and leads to oligonucleosomal DNA fragmentation and advanced chromatin condensation and the other which is caspase-independent.Abstract:
Apaf-1−/− or caspase-3−/− cells treated with a variety of apoptosis inducers manifest apoptosis-associated alterations including the translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, large scale DNA fragmentation, and initial chromatin condensation (stage I). However, when compared with normal control cells, Apaf-1−/− or caspase-3−/− cells fail to exhibit oligonucleosomal chromatin digestion and a more advanced pattern of chromatin condensation (stage II). Microinjection of such cells with recombinant AIF only causes peripheral chromatin condensation (stage I), whereas microinjection with activated caspase-3 or its downstream target caspase-activated DNAse (CAD) causes a more pronounced type of chromatin condensation (stage II). Similarly, when added to purified HeLa nuclei, AIF causes stage I chromatin condensation and large-scale DNA fragmentation, whereas CAD induces stage II chromatin condensation and oligonucleosomal DNA degradation. Furthermore, in a cell-free system, concomitant neutralization of AIF and CAD is required to suppress the nuclear DNA loss caused by cytoplasmic extracts from apoptotic wild-type cells. In contrast, AIF depletion alone suffices to suppress the nuclear DNA loss contained in extracts from apoptotic Apaf-1−/− or caspase-3−/− cells. As a result, at least two redundant parallel pathways may lead to chromatin processing during apoptosis. One of these pathways involves Apaf-1 and caspases, as well as CAD, and leads to oligonucleosomal DNA fragmentation and advanced chromatin condensation. The other pathway, which is caspase-independent, involves AIF and leads to large-scale DNA fragmentation and peripheral chromatin condensation.read more
Citations
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TL;DR: This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including ‘entosis’, ‘mitotic catastrophe”,’ ‘necrosis‚ ‘necroptosis‚’ and ‘pyroptotic’.
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References
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Journal ArticleDOI
Molecular characterization of mitochondrial apoptosis-inducing factor
Santos A. Susin,Hans K. Lorenzo,Naoufal Zamzami,Isabel Marzo,Bryan E. Snow,Joan Mangion,Etienne Jacotot,Paola Costantini,Markus Loeffler,Nathanael Larochette,David R. Goodlett,Ruedi Aebersold,David P. Siderovski,Josef M. Penninger,Guido Kroemer +14 more
TL;DR: The identification and cloning of an apoptosis-inducing factor, AIF, which is sufficient to induce apoptosis of isolated nuclei is reported, indicating that AIF is a mitochondrial effector of apoptotic cell death.
Journal ArticleDOI
A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD
Masato Enari,Hideki Sakahira,Hideki Yokoyama,Katsuya Okawa,Akihiro Iwamatsu,Shigekazu Nagata,Shigekazu Nagata +6 more
TL;DR: A caspase-activated deoxyribonuclease (CAD) and its inhibitor (ICAD) have now been identified in the cytoplasmic fraction of mouse lymphoma cells and seems to function as a chaperone for CAD during its synthesis, remaining complexed with CAD to inhibit its DNase activity.
Journal ArticleDOI
Apaf-1, a Human Protein Homologous to C. elegans CED-4, Participates in Cytochrome c–Dependent Activation of Caspase-3
TL;DR: The purification and cDNA cloning of Apaf-1, a novel 130 kd protein from HeLa cell cytosol that participates in the cytochrome c-dependent activation of caspase-3, leading to apoptosis is reported here.
Journal ArticleDOI
DFF, a Heterodimeric Protein That Functions Downstream of Caspase-3 to Trigger DNA Fragmentation during Apoptosis
TL;DR: In this article, the authors identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3.
Journal ArticleDOI
Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis
TL;DR: The results indicate that activation of CAD downstream of the caspase cascade is responsible for internucleosomal DNA degradation during apoptosis, and that ICAD works as an inhibitor of this process.