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

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 rat...

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Bibliographic Details
Published in:The Journal of cell biology 2005-02, Vol.168 (4), p.553-560
Main Authors: Maehara, Kayoko, Yamakoshi, Kimi, Ohtani, Naoko, Kubo, Yoshiaki, Takahashi, Akiko, Arase, Seiji, Jones, Nic, Hara, Eiji
Format: Article
Language:English
Subjects:
Antibodies
Cancer
Cell cycle
Cell Cycle - physiology
Cell Cycle Proteins - metabolism
Cell growth
Cell lines
Cell Proliferation
Cellular biology
Cellular senescence
Cellular Senescence - physiology
Chromatin Immunoprecipitation
DNA-Binding Proteins - metabolism
E2F Transcription Factors
Electrophoretic Mobility Shift Assay
Epithelial cells
HeLa Cells
HT29 cells
Humans
Proteins
Retinoblastoma Protein - deficiency
Retinoblastoma Protein - metabolism
Retroviridae
RNA Interference - physiology
Signal Transduction - physiology
Transcription Factor DP1
Transcription Factors - metabolism
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - deficiency
Tumor Suppressor Protein p53 - metabolism
Tumors
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Summary: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.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200411093