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Journal of Virology, May 2004, p. 4646-4654, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4646-4654.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Expression of an E1A/E7 Chimeric Protein Sensitizes Tumor Cells to Killing by Activated Macrophages but Not NK Cells

Tanya A. Miura,¹ Han Li,¹ Kristin Morris,¹ Sharon Ryan,¹ Kristine Hembre,¹ James L. Cook,² and John M. Routes^1,3*

Departments of Medicine and Immunology, National Jewish Medical and Research Center, Denver, Colorado 80206,¹ Departments of Medicine and Microbiology-Immunology and the Cancer Center, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612,² Departments of Medicine and Immunology and the Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80262³

Received 13 November 2003/ Accepted 31 December 2003

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.

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* Corresponding author. Mailing address: Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Phone: (303) 398-1291. Fax: (303) 398-1806. E-mail: routesj{at}njc.org.

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Journal of Virology, May 2004, p. 4646-4654, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4646-4654.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Routes, J. M., Ryan, S., Morris, K., Takaki, R., Cerwenka, A., Lanier, L. L. (2005). Adenovirus serotype 5 E1A sensitizes tumor cells to NKG2D-dependent NK cell lysis and tumor rejection. JEM 202: 1477-1482 [Abstract] [Full Text]  
• Routes, J. M., Morris, K., Ellison, M. C., Ryan, S. (2005). Macrophages Kill Human Papillomavirus Type 16 E6-Expressing Tumor Cells by Tumor Necrosis Factor Alpha- and Nitric Oxide-Dependent Mechanisms. J. Virol. 79: 116-123 [Abstract] [Full Text]