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J. Biol. Chem., Vol. 277, Issue 52, 50820-50827, December 27, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/52/50820    most recent M208557200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rohn, J. L. Articles by Noteborn, M. H. M. Search for Related Content PubMed PubMed Citation Articles by Rohn, J. L. Articles by Noteborn, M. H. M. Social Bookmarking                      What's this?

A Tumor-specific Kinase Activity Regulates the Viral Death Protein Apoptin^*

Jennifer L. Rohn, Ying-Hui Zhang, Remco I. J. M. Aalbers^§, Norbert Otto^¶, Jeroen den Hertog, Niek V. Henriquez, Cornelis J. H. van de Velde^§, Peter J. K. Kuppen^§, Dominik Mumberg^¶, Peter Donner^¶, and Mathieu H. M. Noteborn^**

From  Leadd B.V., 2300 RA Leiden, the Netherlands, ^§ Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, the Netherlands, ^¶ Research Laboratories of Schering AG, D-13342 Berlin, Germany,  Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, the Netherlands, and ^** Department of Molecular Cell Biology, Leiden University Medical Center, 2300 RA Leiden, the Netherlands

Apoptin, a chicken anemia virus-encoded protein, is thought to be activated by a general tumor-specific pathway, because it induces apoptosis in a large number of human tumor or transformed cells but not in their normal, healthy counterparts. Here, we show that Apoptin is phosphorylated robustly both in vitro and in vivo in tumor cells but negligibly in normal cells, and we map the site to threonine 108. A gain-of-function point mutation (T108E) conferred upon Apoptin the ability to accumulate in the nucleus and kill normal cells, implying that phosphorylation is a key regulator of the tumor-specific properties of Apoptin. An activity that could phosphorylate Apoptin on threonine 108 was found specifically in tumor and transformed cells from a variety of tissue origins, suggesting that activation of this kinase is generally associated with the cancerous or pre-cancerous state. Moreover, analyses of human tissue samples confirm that Apoptin kinase activity is detectable in primary malignancies but not in tissue derived from healthy individuals. Taken together, our results support a model whereby the dysregulation of the cellular pathway leading to the phosphorylation of Apoptin contributes to human tumorigenesis.

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