Faculty Collaboration Database

Expression of an E1A/E7 chimeric protein sensitizes tumor cells to killing by activated macrophages but not NK cells. J Virol 2004 May;78(9):4646-54

Date

04/14/2004

Pubmed ID

15078947

Pubmed Central ID

PMC387719

DOI

10.1128/jvi.78.9.4646-4654.2004

Scopus ID

2-s2.0-10644248516 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

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.

Author List

Miura TA, Li H, Morris K, Ryan S, Hembre K, Cook JL, Routes JM

Author

John M. Routes MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenovirus E1A Proteins
Animals
Cytotoxicity, Immunologic
Humans
Killer Cells, Natural
Macrophage Activation
Macrophages
Mice
Mice, Inbred C57BL
Oncogene Proteins, Viral
Papillomaviridae
Rats
Recombinant Fusion Proteins
Tumor Cells, Cultured