Adenovirus (Ad) E1A and human papillomavirus (HPV) E7 express homologous conserved regions (CRs) that mediate their shared biological functions. Despite their similarities, the expression of E1A sensitizes tumor cells to killing by NK cells and macrophages but the expression of E7 does not, a factor that may contribute to the dissimilar oncogenicities of Ad and HPV. This study was undertaken to define molecular differences between E1A and E7 that are responsible for the ability of E1A and the inability of E7 to sensitize cells to killing by NK cells and macrophages. Genetic mapping studies using human fibrosarcoma cells (H4) that stably expressed mutant forms of E1A showed that only those forms of E1A that interacted with the transcriptional coadaptor protein p300 sensitized cells to killing by NK cells and macrophages. E7 lacks the N-terminal p300-binding region present in E1A. Therefore, a chimeric E1A/E7 gene was constructed that included the N terminus and the CR1 (p300-binding) domain of E1A fused to CR2 and the C-terminal sequences of E7. The E1A/E7 protein interacted with p300 and pRb and immortalized primary mouse embryo fibroblasts (MEF). The expression of E1A/E7 sensitized H4 and MEF cells to killing by activated macrophages but not to killing by NK cells. Therefore, N-terminal differences between E1A and E7 that map to the E1A-p300 binding region accounted for differences in their abilities to sensitize cells to killing by macrophages. However, regions in addition to the E1A-p300 binding region are required to sensitize cells to killing by NK cells.Adenoviruses (Ad) and human papillomaviruses (HPV) are common human pathogens that express functionally analogous oncoproteins. Two viral oncoproteins are consistently expressed upon cellular transformation in HPV-induced malignancies or Ad-transformed cells (HPV E7 and E6; Ad E1A and E1B). The E1A and E7 oncoproteins express homologous conserved regions (CRs), CR1 and CR2. These CRs interact with and inhibit cellular growth regulatory proteins (pRb, p107, p130, and cyclin A) (20,27,(37)(38)(39)(40)52). CR1 and CR2 of E1A and E7 are interchangeable for cellular immortalization (6). Through different molecular mechanisms, the Ad E1B-55K and HPV E6 oncoproteins inhibit the function of p53, thereby complementing E1A and E7 in inducing cellular transformation.Despite the functional similarities in their transforming oncoproteins, Ad do not appear to be oncogenic in humans. In contrast, HPV are responsible for Ͼ95% of cervical carcinomas (5, 25). The inability of Ad to be oncogenic in humans is notable because Ad are fully competent to transform human cells (24) and Ad-transformed human cells form tumors in immunodeficient mice (13). These observations suggest that factors in addition to cellular transformation by Ad or HPV determine the oncogenicity of these viruses.The difference in the abilities of E1A and E7 to elicit an antitumor immune response is one factor that likely contributes to the dissimilar oncogenicities of Ad and HPV. In immunocompetent mice, tu...