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Published 14 February 2005. doi:10.1083/jcb.200411093
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 4, 553-560
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 Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53

Kayoko Maehara1, Kimi Yamakoshi2, Naoko Ohtani2, Yoshiaki Kubo3, Akiko Takahashi2, Seiji Arase3, Nic Jones1, and Eiji Hara1,2

1 Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, England, UK
2 Division of Protein Information, Institute for Genome Research
3 Department of Dermatology, School of Medicine, University of Tokushima, Tokushima 770-8503, Japan

Correspondence to Eiji Hara: hara{at}genome.tokushima-u.ac.jp


Abstract
E2F/DP complexes were originally identified as potent transcriptional activators required for cell proliferation. However, recent studies revised this notion by showing that inactivation of total E2F/DP activity by dominant-negative forms of E2F or DP does not prevent cellular proliferation, but rather abolishes tumor suppression pathways, such as cellular senescence. These observations suggest that blockage of total E2F/DP activity may increase the risk of cancer. Here, we provide evidence that depletion of DP by RNA interference, but not overexpression of dominant-negative form of E2F, efficiently reduces endogenous E2F/DP activity in human primary cells. Reduction of total E2F/DP activity results in a dramatic decrease in expression of many E2F target genes and causes a senescence-like cell cycle arrest. Importantly, similar results were observed in human cancer cells lacking functional p53 and pRB family proteins. These findings reveal that E2F/DP activity is indeed essential for cell proliferation and its reduction immediately provokes a senescence-like cell cycle arrest.

Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; dn, dominant negative; EMSA, electrophoretic mobility shift assay; HDF, human diploid fibroblast; pRB, retinoblastoma protein; RNAi, RNA interference; SA-ß-gal, senescence-associated ß-galactosidase; SAHF, senescence-associated heterochromatic foci; shRNA, small hairpin RNA.


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