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A more recent version of this article appeared on December 20, 2002
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M208557200v1
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Papers In Press, published online ahead of print October 21, 2002
J. Biol. Chem, 10.1074/jbc.M208557200
Submitted on August 21, 2002
Revised on October 3, 2002
Accepted on October 21, 2002

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

Leadd, Leiden 2300 RA

Corresponding Author: rohn{at}leadd.nl

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 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 Apoptin’s tumor-specific properties. 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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