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Journal of Virology, August 2000, p. 7072-7078, Vol. 74, No. 15
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Chicken Anemia Virus-Derived Protein Apoptin Requires Activation of Caspases for Induction of Apoptosis in Human Tumor Cells

A. A. A. M. Danen-van Oorschot,1,2 A. J. van der Eb,1,dagger and M. H. M. Noteborn1,2,*

Department of Molecular Cell Biology, Leiden University Medical Center,1 and Leadd BV,2 Leiden, The Netherlands

Received 26 October 1999/Accepted 26 April 2000

The chicken anemia virus protein Apoptin has been shown to induce apoptosis in a large number of transformed and tumor cell lines, but not in primary cells. Whereas many other apoptotic stimuli (e.g., many chemotherapeutic agents and radiation) require functional p53 and are inhibited by Bcl-2, Apoptin acts independently of p53, and its activity is enhanced by Bcl-2. Here we study the involvement of caspases, an important component of the apoptotic machinery present in mammalian cells. Using a specific antibody, active caspase-3 was detected in cells expressing Apoptin and undergoing apoptosis. Although Apoptin activity was not affected by CrmA, p35 did inhibit Apoptin-induced apoptosis, as determined by nuclear morphology. Cells expressing both Apoptin and p35 showed only a slight change in nuclear morphology. However, in most of these cells, cytochrome c is still released and the mitochondria are not stained by CMX-Ros, indicating a drop in mitochondrial membrane potential. These results imply that although the final apoptotic events are blocked by p35, parts of the upstream apoptotic pathway that affect mitochondria are already activated by Apoptin. Taken together, these data show that the viral protein Apoptin employs cellular apoptotic factors for induction of apoptosis. Although activation of upstream caspases is not required, activation of caspase-3 and possibly also other downstream caspases is essential for rapid Apoptin-induced apoptosis.

* Corresponding author. Mailing address: Leadd BV, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands. Phone: 31 (0)71 527 8736. Fax: 31 (0)71 527 1736. E-mail: noteborn{at}leadd.nl.

dagger Present address: Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, Leiden, The Netherlands.

Journal of Virology, August 2000, p. 7072-7078, Vol. 74, No. 15
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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