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.
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14 February 2005
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February 14 2005
Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53
Kayoko Maehara,
Kayoko Maehara
1Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, England, UK
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Kimi Yamakoshi,
Kimi Yamakoshi
2Division of Protein Information, Institute for Genome Research
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Naoko Ohtani,
Naoko Ohtani
2Division of Protein Information, Institute for Genome Research
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Yoshiaki Kubo,
Yoshiaki Kubo
3Department of Dermatology, School of Medicine, University of Tokushima, Tokushima 770-8503, Japan
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Akiko Takahashi,
Akiko Takahashi
2Division of Protein Information, Institute for Genome Research
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Seiji Arase,
Seiji Arase
3Department of Dermatology, School of Medicine, University of Tokushima, Tokushima 770-8503, Japan
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Nic Jones,
Nic Jones
1Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, England, UK
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Eiji Hara
Eiji Hara
1Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, England, UK
2Division of Protein Information, Institute for Genome Research
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Kayoko Maehara
1Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, England, UK
Kimi Yamakoshi
2Division of Protein Information, Institute for Genome Research
Naoko Ohtani
2Division of Protein Information, Institute for Genome Research
Yoshiaki Kubo
3Department of Dermatology, School of Medicine, University of Tokushima, Tokushima 770-8503, Japan
Akiko Takahashi
2Division of Protein Information, Institute for Genome Research
Seiji Arase
3Department of Dermatology, School of Medicine, University of Tokushima, Tokushima 770-8503, Japan
Nic Jones
1Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, England, UK
Eiji Hara
1Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, England, UK
2Division of Protein Information, Institute for Genome Research
Correspondence to Eiji Hara: [email protected]
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-β-gal, senescence-associated β-galactosidase; SAHF, senescence-associated heterochromatic foci; shRNA, small hairpin RNA.
Received:
November 16 2004
Accepted:
December 16 2004
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2005
J Cell Biol (2005) 168 (4): 553–560.
Article history
Received:
November 16 2004
Accepted:
December 16 2004
Citation
Kayoko Maehara, Kimi Yamakoshi, Naoko Ohtani, Yoshiaki Kubo, Akiko Takahashi, Seiji Arase, Nic Jones, Eiji Hara; Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53 . J Cell Biol 14 February 2005; 168 (4): 553–560. doi: https://doi.org/10.1083/jcb.200411093
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