Small DNA tumor viruses encode proteins that establish and/or maintain a replication competent cellular milieu to permit replication in differentiated, normally growth arrested host cells. Such induction of aberrant cellular and/or viral DNA synthesis in the absence of concurrent environmental mitogen stimulation causes a situation of conflicting growth signals. This triggers a cellular defense mechanism, the "tropic sentinel response" that eliminates such deviant cells from the proliferative pool through cell-type specific abortive processes such as cell death, differentiation or senescence. Indeed, normal diploid fibroblasts that express single nuclear oncogenes such as adenovirus E1A, c-myc, or human papillomavirus (HPV)-16 E7 undergo cell death when their culture medium is deprived of growth factors. To prevent elimination of their host cells during replication, HPVs encode a complementing function, E6 that neutralizes the tropic sentinel response. While highly effective, such a viral replication strategy is a risky proposition for the host cell. Particularly under conditions of dysregulated viral gene expression that can result from integration of the HPV genome into a host chromosome an infected cell is at increased risk to undergo malignant transformation. The HPV E7 oncoprotein contains at least three molecular determinants, the conserved region 1 homology domain and the pRB binding domains as well as a carboxyl terminal domain that each contribute to the induction of aberrant DNA synthesis. The focus of our research is to identify relevant cellular protein complexes that are targeted through each of these E7 sequences (aims 1 & 2), and to determine the cellular signaling circuits that are triggered to mediate the tropic sentinel response (aim 3). These studies may reveal opportunities for therapeutic modalities designed to unmask the dormant tropic sentinel signal in high-risk HPV associated lesions and cancer.
NIH ExPorter
NIH ExPorter