EXPRESSION OF AP1 DURING CELLULAR-DIFFERENTIATION DETERMINES HUMAN PAPILLOMAVIRUS E6 E7 EXPRESSION IN STRATIFIED EPITHELIAL-CELLS/

E6 and E7 oncoproteins of human papillomavirus (HPV) play significant roles in the pathogenesis of cervical cancer, However, the pattern of E6/E7 expression during the productive virus life cycle in differentia ting epithelia of the uterine cervix remains unclear. In addition, lit tle is known about the cellular factors regulating E6/E7 expression in differentiating epithelia, In the present study, using transient expr ession assays and DNA binding assays, we demonstrated that E6/E7 trans cription is critically regulated by the cellular factor AP1, a Jun/Fos heterodimer complex, Immunohistochemical analyses of various uterine cervical lesions showed AP1 expression in lower cell layers of normal cervix and low-grade cervical intraepithelial neoplasia (CIN), while i t was detected throughout all layers in high-grade CIN and invasive ca ncer. In situ RNA-RNA hybridization analyses of organotypic raft cultu re specimens of an HPV-31-containing cell line revealed that E6/E7 tra nscripts were expressed in most cell layers, with reduced expression i n differentiated cells, This pattern of HPV expression correlated with the pattern of AP1 expression detected by immunohistochemical analyse s, These findings suggest that E6/E7 expression in differentiating epi thelia is dependent on AP1, which appears to be associated with prolif erative activity of the cells, Since E6/E7 expression induces cell pro liferation, co-expression of AP1 and E6/E7 in undifferentiated cell la yers might create a positive regulatory loop, probably contributing to maintenance of initial HPV infection and subsequent activation in bas al and suprabasal cell layers.