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Journal of Virology, August 2006, p. 7535-7545, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.02741-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Apoptin Nucleocytoplasmic Shuttling Is Required for Cell Type-Specific Localization, Apoptosis, and Recruitment of the Anaphase-Promoting Complex/Cyclosome to PML Bodies

Destin W. Heilman, Jose G. Teodoro, and Michael R. Green^*

Howard Hughes Medical Institute and Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts

Received 30 December 2005/ Accepted 10 May 2006

The chicken anemia virus protein Apoptin selectively induces apoptosis in transformed cells while leaving normal cells intact. This selectivity is thought to be largely due to cell type-specific localization: Apoptin is cytoplasmic in primary cells and nuclear in transformed cells. The basis of Apoptin cell type-specific localization and activity remains to be determined. Here we show that Apoptin is a nucleocytoplasmic shuttling protein whose localization is mediated by an N-terminal nuclear export signal (NES) and a C-terminal nuclear localization signal (NLS). Both signals are required for cell type-specific localization, since Apoptin fragments containing either the NES or the NLS fail to differentially localize in transformed and primary cells. Significantly, cell type-specific localization can be conferred in trans by coexpression of the two separate fragments, which interact through an Apoptin multimerization domain. We have previously shown that Apoptin interacts with the APC1 subunit of the anaphase-promoting complex/cyclosome (APC/C), resulting in G₂/M cell cycle arrest and apoptosis in transformed cells. We found that the nucleocytoplasmic shuttling activity is critical for efficient APC1 association and induction of apoptosis in transformed cells. Interestingly, both Apoptin multimerization and APC1 interaction are mediated by domains that overlap with the NES and NLS sequences, respectively. Apoptin expression in transformed cells induces the formation of PML nuclear bodies and recruits APC/C to these subnuclear structures. Our results reveal a mechanism for the selective killing of transformed cells by Apoptin.

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* Corresponding author. Mailing address: Program in Gene Function and Expression, 364 Plantation St., Rm. 628, Worcester, MA 01605. Phone: (508) 856-5330. Fax: (508) 856-5473. E-mail: michael.green{at}umassmed.edu.

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Journal of Virology, August 2006, p. 7535-7545, Vol. 80, No. 15
0022-538X/06/$08.00+0     doi:10.1128/JVI.02741-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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