CELL-TYPE-SPECIFIC ACTIVITY OF THE HUMAN PAPILLOMAVIRUS TYPE-18 UPSTREAM REGULATORY REGION IN TRANSGENIC MICE AND ITS MODULATION BY TETRADECANOYL PHORBOL ACETATE AND GLUCOCORTICOIDS

The upstream regulatory region (URR) of human papillomavirus type 18 ( HPV-18) harbors transcriptional promoter and enhancer elements which a re thought to determine the cell-type specificity of the virus. In ord er to study the regulation of HPV-18 expression in vivo, we constructe d transgenic mice carrying the bacterial lacZ gene under the control o f the HPV-18 URR. Analysis of beta-galactosidase activity by histochem ical staining of tissue sections of four independent transgenic mice s howed that the viral promoter was specifically active in epithelial ce lls within a variety of organs (e.g., tongue, ovary, uterus, testis, a nd small intestine). Very strong staining was observed in newborn tran sgenic mice in contrast to a weak activity found during fetal life. De termination of beta-galactosidase activity in crude extracts from tiss ues of three lines of transgenic mice proved to be a useful tool for a quantitative analysis of transgene expression. In mice from two diffe rent transgenic lines treated with dexamethasone such measurements rev ealed a biphasic effect of the hormone on the activity of the enzyme i n the stratified epithelium of the tongue (transient increase followed by a decrease). Northern (RNA) blot analysis showed similar changes i n beta-galactosidase mRNA in that tissue. Treatment with tetradecanoyl phorbol acetate (TPA) led to a twofold increase in both enzymatic act ivity and mRNA levels. Finally, combined treatments with dexamethasone and TPA showed that both factors interfered with each other in their respective effects on transgene expression, suggesting that a cross-ta lk mechanism between transcription factors could be involved in the re gulation of the HPV-18 URR.