The E2F1–3 transcription factors are essential for cellular proliferation

Wu, Lizhao; Timmers, Cynthia; Maiti, Baidehi; Saavedra, Harold I.; Sang, Ling; Chong, Gabriel T.; Nuckolls, Faison; Giangrande, Paloma H.; Wright, Fred A.; Field, Seth J.; Greenberg, Michael E.; Orkin, Stuart H.; Nevins, Joseph R.; Robinson, Michael L.; Leone, Gustavo

doi:10.1038/35106593

Cited by 548 publications

(503 citation statements)

References 28 publications

Supporting

Mentioning

471

Contrasting

Unclassified

Order By: Relevance

“…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.…”

Section: Cell Cycle Roles Of the Rb Family Of Proteinsmentioning

confidence: 63%

Retinoblastoma family genes

2006

View full text Add to dashboard Cite

Section: Cell Cycle Roles Of the Rb Family Of Proteinsmentioning

confidence: 63%

Retinoblastoma family genes

2006

View full text Add to dashboard Cite

“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

View full text Add to dashboard Cite

Amplification and overexpression of the E2F3 gene at 6p22 in human bladder cancer is associated with increased tumour stage, grade and proliferation index, and in prostate cancer E2F3 overexpression is linked to tumour aggressiveness. We first used small interfering RNA technology to confirm the potential importance of E2F3 overexpression in bladder cancer development. Knockdown of E2F3 expression in bladder cells containing the 6p22 amplicon strongly reduced the extent of bromodeoxyuridine (BrdU) incorporation and the rate of cellular proliferation. In contrast, knockdown of CDKAL1/ FLJ20342, another proposed oncogene, from this amplicon had no effect. Expression cDNA microarray analysis on bladder cancer cells following E2F3 knockdown was then used to identify genes regulated by E2F3, leading to the identification of known E2F3 targets such as Cyclin A and CDC2 and novel targets including pituitary tumour transforming gene 1, Polo-like kinase 1 (PLK1) and Caveolin-2. For both bladder and prostate cancer, we have proposed that E2F3 protein overexpression may cooperate with removal of the E2F inhibitor retinoblastoma tumor suppressor protein (pRB) to drive cellular proliferation. In support of this model, we found that ectopic expression of E2F3a enhanced the BrdU incorporation, a marker of cellular proliferation rate, of prostate cancer DU145 cells, which lack pRB, but had no effect on the proliferation rate of PC3 prostate cancer cells that express wild-type pRB. BrdU incorporation in PC3 cells could, however, be increased by overexpressing E2F3a in cells depleted of pRB. When taken together, these observations indicate that E2F3 levels have a critical role in modifying cellular proliferation rate in human bladder and prostate cancer.

show abstract

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

View full text Add to dashboard Cite

E2F1-3 proteins appear to have distinct roles in progenitor cells and in differentiating cells undergoing cell cycle exit. However, the function of these proteins in paradigms of terminal differentiation that involve continued cell division has not been examined. Using compound E2F1/E2F2-deficient mice, we have examined the effects of E2F1 and E2F2 loss on the differentiation and simultaneous proliferation of bone-marrow-derived cells toward the macrophage lineage. We show that E2F1/ E2F2 deficiency results in accelerated DNA replication and cellular division during the initial cell division cycles of bone-marrow-derived cells, arguing that E2F1/E2F2 are required to restrain proliferation of pro-monocyte progenitors during their differentiation into macrophages, without promoting their cell cycle exit. Accelerated proliferation is accompanied by early expression of DNA replication and cell cycle regulators. Remarkably, rapid proliferation of E2F1/E2F2 compound mutant cultures is temporally followed by induction of a DNA damage response and the implementation of a p21 CIP1 -dependent senescence. We further show that differentiating E2F1/E2F2-knockout macrophages do not trigger a DNA damage response pathway in the absence of DNA replication. These findings underscore the relevance of E2F1 and E2F2 as suppressors of hematopoietic progenitor expansion. Our data indicate that their absence in differentiating macrophages initiates a senescence program that results from enforcement of a DNA damage response triggered by DNA hyper-replication.

show abstract

The E2F1–3 transcription factors are essential for cellular proliferation

Cited by 548 publications

References 28 publications

Retinoblastoma family genes

Retinoblastoma family genes

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

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

Contact Info

Product

Resources

About