“My role as a Ph.D. mentor is to establish an environment that promotes the development of my students to the maximal extent limited only by their talents and desires. A challenging aspect of this role is to avoid simply producing clones of myself but rather help the student identify their talents and professional desires. Toward this end, I believe it is necessary to develop a relationship with each student that allows me to serve in multiple roles: facilitator, adviser, task master, teacher, role model and friend.”

Molecular and Cellular Biology of Adenovirus: an Oncogenic and Oncolytic Virus

The focus of our research concerns adenovirus oncoproteins of early regions 1B (E1B) and 4 (E4). These oncoproteins, which are essential for efficient virus replication, cooperate to immortalize cells and cause tumors in newborn rodents. Two of these—the E1B 55-kilodalton protein and the E4 orf6 protein—act in concert to promote the efficient export of viral mRNA from the nucleus, to block the export of cellular mRNA from the nucleus, and to inactivate key host cell proteins that regulate cell growth and DNA repair. Our work suggests that these viral proteins operate through host cell factors normally involved in mRNA transport. We have mapped one factor to a small region of human chromosome 21 corresponding to the RUNX1 gene. Ongoing work seeks to identify the contribution of RUNX1 to the outcome of an adenovirus infection.

The E1B 55-kilodalton and the E4 orf6 oncoproteins are also required for adenovirus to replicate in a cell cycle-independent manner. This observation forms a second, related focus of our research. Mutant adenoviruses that cannot regulate messenger RNA transport are able to replicate only by infecting a cell that is in S phase. The control of both mRNA transport and translation are linked to the cell cycle at the time of infection. We have discovered that the ability to selectively replicate in the S-phase-infected cell is influenced by other oncoproteins of the E4 region. By studying the cellular processes targeted by these oncoproteins for efficient virus replication, we gain a greater understanding of fundamental mechanisms of cellular growth targeted by adenovirus. This property has lead to the use of the E1B 55-kilodalton-mutant virus to treat several forms of human cancer. Our research provides information needed for the rational design and application of such conditionally replicating, oncolytic adenoviruses.

Publications

Marshall LJ, Moore AC, Ohki M, Kitabayashi K, Patterson D, and Ornelles DA. (2008) RUNX1 permits E4orf6-directed nuclear localization of the adenovirus E1B-55K protein and associates with centers of viral DNA and RNA synthesis. J Virol 82:6395-6408.

Gustafsson B, H Wen, Bogdanovic G, Gauffin F, Nordgren A, Talekar G, Ornelles DA and Gooding LR  (2007) Adenovirus DNA is detected at increased frequency in Guthrie cards from children who develop acute lymphoblastic leukaemia. Brit J Cancer 97:992-994.

Hart LS, Ornelles DA, and Koumenis C. (2006) The adenoviral E4ORF6 protein induces atypical apoptosis in response to DNA damage. J Biol Chem. 282:6061-6067.

Shapiro GS, Van Peursem C, Ornelles DA, Schaack J, and DeGregori J. (2006)  Recombinant adenoviral vectors can induce expression of p73 via the E4orf6/7 protein. J Virol. 80:5349-5360.

Weitzman MD, Ornelles DA. 2005. Inactivating intracellular antiviral responses during adenovirus infection. Oncogene. 24:7686-7696.

Hart LS, Yannone SM, Naczki C, Orlando JS, Waters SB, Akman SA, Chen DJ, Ornelles D, Koumenis C. 2005. The adenovirus E4orf6 protein inhibits DNA double strand break repair and radiosensitizes human tumor cells in an E1B-55K-independent manner. J Biol Chem. 280:1474-1781.

Shepard RN, Ornelles DA. 2004. Diverse roles for E4orf3 at late times of infection revealed in an E1B 55-kilodalton protein mutant background. J Virol. 2004. 78:9924-9935.

PubMed link to Ornelles DA