Activation of the tumor-specific death effector apoptin and its kinase by an N-terminal determinant of simian virus 40 large T antigen.
Apoptin, a viral death protein derived from chicken anemia virus, displays a number of tumor-specific behaviors. In particular, apoptin is phosphorylated, translocates to the nucleus, and induces apoptosis specifically in tumor or transformed cells, whereas it is nonphosphorylated and remains primarily inactive in the cytoplasm of nontransformed normal cells. Here, we show that in normal cells apoptin can also be activated by the transient transforming signals conferred by ectopically expressed simian virus 40 (SV40) large T antigen (LT), which rapidly induces apoptin's phosphorylation, nuclear accumulation, and the ability to induce apoptosis. Further analyses with mutants of LT showed that the minimum domain capable of inducing all three of apoptin's tumor-specific properties resided in the N-terminal J domain, a sequence which is largely shared by SV40 small t antigen (st). Interestingly, the J domain in st, which lacks its own nuclear localization signal (NLS), required nuclear localization to activate apoptin. These results reveal the existence of a cellular pathway shared by conditions of transient transformation and the stable cancerous or precancerous state, and they support a model whereby a transient transforming signal confers on apoptin both the upstream activity of phosphorylation and the downstream activity of nuclear accumulation and apoptosis induction. Such a pathway may reflect a general lesion contributing to human cancers.
Zhang
Ying-Hui
YH
Leadd B.V., Leiden, The Netherlands.
Kooistra
Klaas
K
Pietersen
Alexandra
A
Rohn
Jennifer L
JL
Noteborn
Mathieu H M
MH
D000595:Amino Acid Sequence; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D036022:Capsid Proteins / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000821:virology; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D017727:Chicken anemia virus / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D051379:Mice; D009154:Mutation; D017434:Protein Structure, Tertiary; D013539:Simian virus 40 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*
D000952:Antigens, Polyomavirus Transforming; D036022:Capsid Proteins; C091717:VP3 protein, Chicken anemia virus