The larger focus of our research is to elucidate the role of cellular growth-regulatory mechanisms in virus replication and viral pathogenesis. Late during an adenovirus infection, host cell mRNA fails to reach the cytoplasm while viral mRNA is successfully transported from the nucleus to the cytoplasm. A complex composed of at least two adenovirus gene products, the E1B-55K tumor antigen and the E4orf6 oncoprotein, promotes the transport of viral mRNA and simultaneously prevents the transport of host cell mRNA.
Adenovirus mutants that cannot reprogram mRNA transport are restricted for growth in a cell cycle-dependent manner. By infecting synchronized cells, we found that the mRNA transport defect is apparent corrected when these mutant viruses infect a cell in S phase. Additionally, the translation of both viral and cellular mRNA is regulated in a cell cycle-dependent manner. The cell cycle-restriction is normally overcome by the cooperation of viral proteins such as the E1B-55K and E4orf6 proteins. Still other viral products may actually elicit the cell cycle-restriction itself.
Our work suggests that the E1B-55K and E4orf6 viral proteins operate through host cell factors normally involved in mRNA transport and cell cycle control. One goal of our research is to identify these cellular factors. Another goal of our research is to understand the link between the cell cycle, mRNA transport, and translation. Finally, this work has provided a rational basis for the use of the E1B-55K mutant adenovirus in the treatment of cancer. |
Recent Publications (selected):
Goodrum FD, Ornelles DA.: Roles for the E4 orf6, orf3, and E1B 55-kilodalton proteins in cell cycle-independent adenovirus replication. J. Virol. 73:7474-88 (1999).
Orlando JS, Ornelles DA.: An arginine-faced amphipathic alpha helix is required for adenovirus type 5 e4orf6 protein function. J. Virol. 73:4600-10 (1999).
Goodrum FD, Ornelles DA.: p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection. J. Virol. 72:9479-90 (1998).
Goodrum FD, Ornelles DA.: The early region 1B 55-kilodalton oncoprotein of adenovirus relieves growth restrictions imposed on viral replication by the cell cycle. J. Virol. 71:548-61 (1997). |