This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Invasive cervical carcinoma and precursor lesions are strongly associated with the presence of human papillomavirus (HPV) infection, particularly the PHV16 type. HPV16 expresses three oncogenes - E5, E6, and E7. The proteins encoded by the E6 and E7 oncogenes have been shown to inhibit the function of the tumor suppressor genes p53 and Rb, respectively (CITE). Despite numberous lines of evidence that expression of E5 can cause cell transformation, the mechanism by which this occurs has been controversial. We have recently discovered that the expression of HPV16 E5 protein can induce cell-cell fusion resulting in bi-nucleated cells, enlarged nuclei, and tetraploidy. Interestingly, these are all characteristics of cancerous and precursor lesions. Based on these findings and the work of others, we hypothesize that E5 initiates tumorigenesis by inducing cell-cell fusion and subsequent instability in chromosome content. HOwever, the molecular mechanisms that underlie these fusion events are still unclear. We propose to verify and extend our in vitro findings by developing and in vivo model of HPV E5 function using Drosophila melanogaster as a model organism. We will develop a transgenic Drosophila model to characterize the phenotypic consequences of HPV16 E5 expression. We will first look at the effect of ubiquitous HPV16 E5 expression during Drosophila development. Next, we will express HPV16 E5 specifically in Drosophila epithelial cells i vivo to test whether PHV16 E5 expression can induce aberrant cell morphologies thatare associated with cancer. These experiments will help to establish an invivo model of the HPV16 E5 gene that will allow future work toward elucidating the genetic and cellular determinants of HPV-induced carcinogenesis.
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