A tumor-specific kinase activity regulates the viral death protein Apoptin.
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.
Rohn
Jennifer L
JL
Leadd B.V., 2300 RA Leiden, The Netherlands.
Zhang
Ying-Hui
YH
Aalbers
Remco I J M
RI
Otto
Norbert
N
Den Hertog
Jeroen
J
Henriquez
Niek V
NV
Van De Velde
Cornelis J H
CJ
Kuppen
Peter J K
PJ
Mumberg
Dominik
D
Donner
Peter
P
Noteborn
Mathieu H M
MH
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002213:Capsid / Q000737:chemistry / Q000378:metabolism*; D036022:Capsid Proteins; D002478:Cells, Cultured; D017727:Chicken anemia virus; D014644:Genetic Variation; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D010449:Peptide Mapping; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014407:Tumor Cells, Cultured
D036022:Capsid Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C091717:VP3 protein, Chicken anemia virus; D010768:Phosphoserine; D011494:Protein Kinases