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Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53

Authors :
Kimi Yamakoshi
Nic Jones
Seiji Arase
Kayoko Maehara
Yoshiaki Kubo
Akiko Takahashi
Naoko Ohtani
Eiji Hara
Source :
The Journal of Cell Biology
Publication Year :
2005
Publisher :
Rockefeller University Press, 2005.

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.

Details

ISSN :
15408140 and 00219525
Volume :
168
Database :
OpenAIRE
Journal :
Journal of Cell Biology
Accession number :
edsair.doi.dedup.....a8237ed3403fbb8fbb8a59d8671edc82
Full Text :
https://doi.org/10.1083/jcb.200411093