AUTOREGULATORY CONTROL OF E2F1 EXPRESSION IN RESPONSE TO POSITIVE AND NEGATIVE REGULATORS OF CELL-CYCLE PROGRESSION

Both positive and negative signals govern the progression of cells from G(1) into S phase, and a variety of data implicate the E2F transcription factor as a target for the action of one class of negative regulators, the Rb family of growth suppressors. We now find that the E2F1 gene, which encodes one of the components of E2F activity, is subject to autoregulatory control during progression from G(0) to S phase and that this primarily reflects a negative control in G(0) and early G(1), a time when the majority of E2F activity exits as a complex with Rb family members. In addition, we find that deregulated expression of G(1), cyclins in quiescent cells stimulates the E2F1 promoter and that this is augmented by coexpression of cyclin-dependent kinases in an E2F-dependent manner. We conclude that the E2F1 gene is a downstream target for G(1) cyclin dependent kinase activity, most likely as a consequence of phosphorylation of Rb family members, and that the autoregulation of E2F1 transcription may provide a sensitive switch for regulating the accumulation of E2F activity during the transition from G(1) to S phase.