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First published online 15 March 2006
doi: 10.1242/dev.02332
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2
1 Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390,
USA.
2 Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska
3, 83306 Bratislava-Kramare, Slovakia.
3 Department of Genetics, Cell Biology and Development, University of Minnesota,
6-160 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
4 Department of Genetics, Faculty of Science, Comenius University, 84215
Bratislava, Slovakia.
5 Department of General Zoology, Lorand Eotvos University, Pazmany setany 1/C,
H-1117 Budapest, Hungary.
6 Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390,
USA.
7 Genome Sciences Centre, BC Cancer Research Centre, 675 West 10th Avenue,
Vancouver, BC V5Z 1L3, Canada.
8 Wellcome Trust, Sanger Institute, Genome Campus, Cambridge CB10 1SA, UK.
* Author for correspondence (e-mail: John.Abrams{at}utsouthwestern.edu)
Accepted 17 February 2006
Histolysis refers to a widespread disintegration of tissues that is morphologically distinct from apoptosis and often associated with the stimulation of autophagy. Here, we establish that a component of the apoptosome, and pivotal regulator of apoptosis, is also required for histolytic cell death. Using in vivo and ex vivo assays, we demonstrate a global apoptogenic requirement for dark, the fly ortholog of Apaf1, and show that a required focus of dark- organismal lethality maps to the central nervous system. We further demonstrate that the Dark protein itself is a caspase substrate and find that alterations of this cleavage site produced the first hypermorphic point mutation within the Apaf1/Ced-4 gene family. In a model of `autophagic cell death', dark was essential for histolysis but dispensable for characteristic features of the autophagic program, indicating that the induction of autophagy occurs upstream or parallel to histolytic cell death. These results demonstrate that stimulation of autophagy per se is not a `killing event' and, at the same time, establish that common effector pathways, regulated by the apoptosome, can underlie morphologically distinct forms of programmed cell death.
Key words: Autophagy, Apoptosis, Drosophila, Histolysis, dark
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