Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry.

ABSTRACT

Deregulation of the retinoblastoma protein (pRB) pathway is a hallmark of cancer. In the absence of other genetic alterations, this deregulation results in lack of differentiation, hyperproliferation and apoptosis. The pRB protein acts as a transcriptional repressor by targeting the E2F transcription factors, whose functions are required for entry into S phase. Increased E2F activity can induce S phase in quiescent cells--this is a central element of most models for the development of cancer. We show that although E2F1 alone is not sufficient to induce S phase in diploid mouse and human fibroblasts, increased E2F1 activity can result in S-phase entry in diploid fibroblasts in which the p53-mediated G1 checkpoint is suppressed. In addition, we show that E2F1 can induce S phase in primary mouse fibroblasts lacking pRB. These results indicate that, in addition to acting as an E2F-dependent transcriptional repressor, pRB is also required for the cells to retain the G1 checkpoint in response to unprogrammed proliferative signals.