The tumor cell specific nuclear targeting signal of Apoptin

Chicken Anemia Virus viral protein 3 (VP3 or apoptin)’s ability to localize preferentially to the nucleus of tumor but not normal cells is tightly linked to its ability to be exclusively phosphorylated in tumor but not normal cells at residue T108. The link between apoptin’s phosphorylation state and subcellular localization was recently established with the demonstration that the apoptin C-terminal domain contains a nuclear export sequence (NES), which is inactivated upon phosphorylation in tumor cells. In this review we describe the molecular mechanisms responsible for apoptin's tumor specific nuclear targeting as mediated by its C-terminally located tumor specific nuclear targeting signal (tNTS), formed by a bipartite-like NLS and a phosphorylation-regulated NES, which is sufficient to target heterologous proteins specifically to the nucleus of tumor cells. The potential applications of VP3’s tumor cell-specific nuclear targeting signal in enhancing tumor specificity of non-viral gene therapy approaches are also discussed.