Link of the unique oncogenic properties of adenovirus type 9 E4-ORF1 to a select interaction with the candidate tumor suppressor protein ZO-2

Adenovirus type 9 (Ad9) is distinct among human adenoviruses because it eli cits solely mammary tumors in animals and its primary oncogenic determinant is the E4 region-encoded ORE1 (E4-ORF1) protein. We report here that the P DZ domain-containing protein ZO-2, which is a candidate tumor suppressor pr otein, is a cellular target for tumorigenic Ad9 E4-ORF1 but not for non-tum origenic wild-type E4-ORF1 proteins encoded by adenovirus types 5 and 12. C omplex formation was mediated by the C-terminal PDZ domain-binding motif of Ad9 E4-ORF1 and the first PDZ domain of ZO-2, and in cells this interactio n resulted in aberrant sequestration of ZO-2 within the cytoplasm. Furtherm ore, transformation-defective Ad9 E4-ORF1 mutants exhibited impaired bindin g to and sequestration of ZO-2 in cells, and overexpression of wild-type ZO -2, but not mutant ZO-2 lacking the second and third PDZ domains, interfere d with Ad9 E4-ORF1-induced focus formation. Our results suggest that the se lect capacity to complex with the candidate tumor suppressor protein ZO-2 i s key to defining the unique transforming and tumorigenic properties of the Ad9 E4-ORF1 oncoprotein.