THE CYCLIN E PROMOTER IS ACTIVATED BY HUMAN CYTOMEGALOVIRUS 86-KDA IMMEDIATE-EARLY PROTEIN

Human cytomegalovirus (HCMV) activates cyclin E/Cdk2, which regulates cell cycle progression in G(1) and S phase of the cell cycle. HCMV act ivation of cyclin E/Cdk2 can be demonstrated in cells that are refract ory to normal mitotic stimuli. This observation suggests that the viru s has some means to overcome the stringent control on expression of ce ll cycle progression factors that is characteristic of cells in the G( 0) state. One of the mechanisms involved in activation of cyclin E/Cdk 2 is the induction of cyclin E expression. We report here that HCMV in duces cyclin E expression through a transcriptional mechanism. The cyc lin E gene is activated by the HCMV 86-kDa immediate early gene produc t (IE86), which directly binds to nucleotide sequences within the cycl in E promoter. An IE86 DNA-binding mutant neither binds nor activates the cyclin E promoter. IE86-binding sites within the cyclin E promoter are required for IE86-mediated activation, and deletion of the IE86-b inding site inhibits IE86 activation of the cyclin E promoter. We also demonstrate that mutation of the known E2F-binding sites in the cycli n E promoter does not block activation by HCMV or IE86. These data pro vide a molecular mechanism for HCMV induction of cyclin E and represen t the first report of IE86 directly binding to a cellular promoter.