Megan Spurgeon
BA, University of Missouri - Columbia, 2004
Advisor: Dr. David Ornelles
mespurge@wfubmc.edu 

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Research Interests:

Mutant adenoviruses lacking the E1B-55K gene replicate in and kill tumor cells, but do not kill normal cells. This property is the basis of phase III clinical trials testing the ability of E1B-55K mutant viruses to be utilized as oncolytic agents. The biology of the tumor cell specificity remains poorly understood, although research suggests a relationship with the stage of the cell cycle at the time of infection. E1B-55K mutant viruses are restricted for growth in G1 phase cells, but grow to higher titers, induce efficient cell death, and synthesize more late viral proteins in S phase-infected cells. The amount of late adenoviral mRNA in the cytoplasm and the number of ribosomes per transcript, however, do not account for the level of late viral protein synthesis in S phase-infected cells. Because progeny production and subsequent cell death normally requires late viral protein synthesis, the selectivity of E1B-55K mutant viruses for S phase appears to be functioning at the level of late viral protein synthesis. Protein synthesis during the late phase of adenovirus infection is controlled by a unique, 5’ untranslated region present on all late adenoviral mRNAs. This element, termed the tripartite leader, drives a unique form of translation initiation known as ribosome shunting and allows viral messages to be preferentially translated while cellular translation is diminished.

The goal of the proposed research is to elucidate the molecular mechanism(s) responsible for the S phase selectivity of E1B-55K mutant viruses at the level of late viral protein synthesis. We hypothesize that the rates of ribosome shunting, as well as the cellular and viral effectors of late adenoviral translation, are increased in S phase cells infected with an E1B-55K mutant virus. To directly address this hypothesis, research will be directed by the following two specific aims: 1) The rate of ribosome shunting will be measured in G1 and S phase infected cells, and 2) The levels and phosphorylation of selected factors that influence late adenoviral translation, specifically eIF4G, eIF4E, PABP, and the adenoviral L4-100K protein, will be evaluated in G1 and S phase-infected cells, and the association of these factors with late adenoviral messages in polysomes of infected cells will be measured. Understanding the cell cycle-based selectivity of E1B-55K mutant adenoviruses will provide insight into the function of the E1B-55K protein in translational control. In addition, this research may provide information that could lead to the formation of more selective oncolytic adenoviruses.