CELL-CYCLE REGULATION OF THE CYCLIN-A GENE PROMOTER IS MEDIATED BY A VARIANT E2F SITE

Cyclin A is involved in the control of S phase and mitosis in mammalia n cells, Expression of the cyclin A gene in nontransformed cells is ch aracterized by repression of its promoter during the G(1) phase of the cell cycle and its induction at S-phase entry. We show that this mode of regulation is mediated by the transcription factor E2F, which bind s to a specific site in the cyclin A promoter. It differs from the pro totype E2F site in nucleotide sequence and protein binding; it is boun d by E2F complexes containing cyclin E and p107 but not pRB. Ectopic e xpression of cyclin D1 triggers premature activation of the cyclin A p romoter by E2F, and this effect is blocked by the tumor suppressor pro tein p16(INK4).