MODULATION OF CYCLIN GENE-EXPRESSION BY ADENOVIRUS E1A IN A CELL-LINEWITH E1A-DEPENDENT CONDITIONAL PROLIFERATION

To investigate how adenovirus ELA controls cell proliferation,,fe have fused E1A to the hormone-binding domain of the human estrogen recepto r (ER) and introduced the E1A-ER chimeric gene together with an activa ted ras gene into primary rat embryo fibroblasts. Cell lines derived f rom this transfection proliferate in an estrogen-dependent manner. Est rogen-dependent activation of E1A-ER led to a rapid induction of both cyclin E and cyclin A gene expression. In contrast, levels of cyclin D 1 were strongly reduced by activation of E1A-ER. Similar changes in cy clin gene expression mere observed when primary human fibroblasts were infected with wild-type adenovirus and when adenovirus E1A was stably expressed in NIH 3T3 cells. Our findings suggest that activation of c yclin A and E, but not D1, gene expression by E1A precedes and may be responsible for E1A-dependent cell proliferation. In contrast, we foun d that quantitative disruption of complexes between the E2F transcript ion factor and the retinoblastoma protein is not required for E1A-depe ndent S-phase entry.