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The many different serotypes of human adenoviruses (Ad) are divided into six subgroups, of which all Ad subgroup A and B and two subgroup D Ads can elicit tumors in infected rodents. Unlike the Ads from subgroup A and B, the ones from subgroup D, Ad9 and Ad10 elicit estrogen-dependent mammary tumors as opposed to undifferentiated sarcomas. In the case of Ad9, its tumorigenicity is dependent on the product of the open reading frame (ORF) 1 of the early region 4 (E4). The tumorigenic potential of Ad9 E4 Orf1 depends on a carboxyl-terminal PDZ domain-binding motif that mediates interactions with several different membrane-associated cellular proteins such as MUPP1, PATJ, MAGI-1, ZO-2 and Dlg1. It has been suggested that Ad9 E4 Orf1 may have evolved from an ancestral cellular dUTP pyrophosphatase.
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