Cervical cancer is one of the leading causes of death from cancer in women. Cervical cancer is preceded by an abnormal form of growth known as dysplasia. The long term goal of the project is to elucidate the molecular events necessary for the development of cervical malignancy. The project will pursue 2 approaches to this issue. Human papillomavirus (HPV) has been strongly implicated as an etiological agent in the development of cervical cancer. The products of two viral genes, E6 and E7, have been implicated in the development of cervical cancer, at least in part through their ability to bind to tumor suppressor genes. Their role in the development of cervical dysplasia is unknown.
One aim of this proposal is to elucidate the cellular target genes of HPV16 E7. The approach involves the use of an inducible form of E7 to generate two populations of cells which differ only in the state of activation of E7. RNA from these populations will be compared by differential display to identify cellular transcripts induced or repressed by the action of E7. The nature of these transcripts will be characterized by sequencing and analysis of expression through the cell cycle. The role of E7 target genes in the development of dysplasia will be examined through the use of in situ hybridization on normal, dysplastic and malignant tissue specimens. The second approach of the project is to determine other genes important in the development of dysplasia, using organotypic cultures of keratinocytes as a source of RNA. Once mRNA transcripts specific to dysplasia have been identified, they will be characterized in a similar fashion to the E7 target genes. In the long term, it is hoped that the identification of mRNA transcripts involved in the development of dysplasia will generate a set of markers that will assist in the appropriate management of dysplastic lesions and will provide clues for therapeutic intervention.
| Smith-McCune, K; Kalman, D; Robbins, C et al. (1999) Intranuclear localization of human papillomavirus 16 E7 during transformation and preferential binding of E7 to the Rb family member p130. Proc Natl Acad Sci U S A 96:6999-7004 |
