Cyclin A Is a Mediator of p120^E4F-Dependent Cell Cycle Arrest in G₁

Abstract

E4F is a ubiquitously expressed GLI-Krüppel-related transcription factor which has been identified for its capacity to regulate transcription of the adenovirus E4 gene in response to E1A. However, cellular genes regulated by E4F are still unknown. Some of these genes are likely to be involved in cell cycle progression since ectopic p120 ^E4F expression induces cell cycle arrest in G₁. Although p21 ^WAF1 stabilization was proposed to mediate E4F-dependent cell cycle arrest, we found that p120 ^E4F can induce a G₁ block in p21^−/− cells, suggesting that other proteins are essential for the p120 ^E4F -dependent block in G₁. We show here that cyclin A promoter activity can be repressed by p120 ^E4F and that this repression correlates with p120 ^E4F binding to the cyclic AMP-responsive element site of the cyclin A promoter. In addition, enforced expression of cyclin A releases p120 ^E4F -arrested cells from the G₁block. These data identify the cyclin A gene as a cellular target for p120 ^E4F and suggest a mechanism for p120 ^E4F -dependent cell cycle regulation.

ACKNOWLEDGMENTS

We thank R. Hipskind, A. Le Cam, and V. Coulon for critical comments on the manuscript.

This work was funded by grants from CNRS (ATIPE 3), l'Association pour le Recherche contre le Cancer, La Ligue Contre le Cancer, and the Human Frontier Science Program. L.F. was supported by a EEC/TMR postdoctoral fellowship.