The E2F1–3 transcription factors are essential for cellular proliferation

Abstract

The retinoblastoma tumour suppressor (Rb) pathway is believed to have a critical role in the control of cellular proliferation by regulating E2F activities. E2F1, E2F2 and E2F3 belong to a subclass of E2F factors thought to act as transcriptional activators important for progression through the G1/S transition. Here we show, by taking a conditional gene targeting approach, that the combined loss of these three E2F factors severely affects E2F target expression and completely abolishes the ability of mouse embryonic fibroblasts to enter S phase, progress through mitosis and proliferate. Loss of E2F function results in an elevation of p21Cip1 protein, leading to a decrease in cyclin-dependent kinase activity and Rb phosphorylation. These findings suggest a function for this subclass of E2F transcriptional activators in a positive feedback loop, through down-modulation of p21Cip1, that leads to the inactivation of Rb-dependent repression and S phase entry. By targeting the entire subclass of E2F transcriptional activators we provide direct genetic evidence for their essential role in cell cycle progression, proliferation and development.

Retinoblastoma family genes

“…Compound knockout of E2Fs 1-3 leads to cell cycle arrest of mouse embryonic fibroblasts (MEFs) with an accumulation of the cdk inhibitor p21 (Wu et al, 2001). This is similar to RNAi knock-down of dE2F1 in Drosophila SL2 cells , supporting the notion of a conserved role for the activating E2F proteins.…”

Role of E2F3 expression in modulating cellular proliferation rate in human bladder and prostate cancer cells

“…Mouse embryo fibroblasts (MEFs) with a defect in the E2F3 gene (E2F3À/À) have a proliferative and cell cycle defect when compared to their wild-type counterparts and at a critical threshold level, E2F3-controlled genes appear to determine the time of the G1/S transition (Leone et al, 1998;Humbert et al, 2000;Wu et al, 2001). Additionally, microinjection of E2F3 antibodies into the MEFs impairs entry into S phase (Leone et al, 1998).…”

Accelerated DNA replication in E2F1- and E2F2-deficient macrophages leads to induction of the DNA damage response and p21CIP1-dependent senescence

“…Furthermore, knockout of E2F1 in mouse embryo fibroblasts or in T lymphocytes modestly slows progression from quiescence to S phase (Wang et al, 1998;Murga et al, 2001), and E2F2 À/À and E2F1/E2F2 À/À mice exhibit impaired hematopoiesis resulting from defective S-phase progression in progenitor populations (Li et al, 2003). The combined inactivation of E2F1, 2 and 3 completely abolishes entry into S phase and proliferation, along with reduced expression of E2F target genes necessary for these processes (Wu et al, 2001). These results argue for a positive role for E2F1-3 in cell cycle progression.…”