The C-terminus of apoptin represents a unique tumor cell-enhanced nuclear targeting module

Chicken anemia virus viral protein 3 (VP3 or apoptin) localizes more efficiently in the nucleus of transformed than nontransformed cells. Although previous studies implicate the C-terminus of apoptin as being responsible, the molecular basis is controversial, and the extent to which altered nuclear transport efficiency in tumor cells may influence VP3 differential targeting unclear. Here we establish that the C-terminus of VP3 (residues 74-121), out of the context of the full-length protein, is indeed sufficient for tumor cell-enhanced nuclear targeting through phosphoinhibition of VP3 (74-121)-mediated nuclear export occurring exclusively in tumor cells. Importantly, we show that VP3 (74-121) is unique in showing tumor cell-enhanced nuclear targeting in that other NLS-containing proteins fail to show differential localization in human osteosarcoma cells compared to their normal isogenic counterparts. Thus, the C-terminus of VP3 represents a unique tumor cell-enhanced nuclear targeting module with potential application in tumor cell-specific drug delivery.