Importance of nuclear localization of apoptin for tumor-specific induction of apoptosis

Astrid A.A.M. Danen-Van Oorschot, Ying Hui Zhang, S. Rutger Leliveld, Jennifer L. Rohn, Maud C.M.J. Seelen, Marian W. Bolk, Arend Van Zon, Stefan J. Erkeland, Jan Pieter Abrahams, Dominik Mumberg, Mathieu H.M. Noteborn*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

140 Citations (Scopus)
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Abstract

The chicken anemia virus-derived protein Apoptin induces apoptosis specifically in human tumor and transformed cells and not in normal, untransformed cells. The cell killing activity correlates with a predominantly nuclear localization of Apoptin in tumor cells, whereas in normal cells, it is detected mainly in cytoplasmic structures. To explore the role of nuclear localization for Apoptin-induced cell death in tumor cells, we employed a mutagenesis strategy. First, we demonstrated that the C terminus of Apoptin contains a bipartite-type nuclear localization signal. Strikingly, further investigation showed that Apoptin contains two different domains that induce apoptosis independently, and for both domains, we found a strong correlation between localization and killing activity. Using inhibitors, we ruled out the involvement of de novo gene transcription and translation and further showed that Apoptin itself does not have any significant transcriptional repression activity, suggesting that Apoptin exerts its effects in the nucleus by some other method. To determine whether nuclear localization is sufficient to enable Apoptin to kill normal, untransformed cells, we expressed full-length Apoptin fused to a heterologous nuclear localization signal in these cells. However, despite its nuclear localization, no apoptosis was induced, which suggests that nuclear localization per se is not sufficient for Apoptin to become active. These studies increase our understanding of the molecular pathway of Apoptin and may also shed light on the mechanism of cellular transformation.

Original languageEnglish
Pages (from-to)27729-27736
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number30
DOIs
Publication statusPublished - 25 Jul 2003
Externally publishedYes

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