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 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.
Maehara
Kayoko
K
Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, England, UK.
Yamakoshi
Kimi
K
Ohtani
Naoko
N
Kubo
Yoshiaki
Y
Takahashi
Akiko
A
Arase
Seiji
S
Jones
Nic
N
Hara
Eiji
E
D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D024202:Electrophoretic Mobility Shift Assay; D006367:HeLa Cells; D006801:Humans; D034622:RNA Interference / Q000502:physiology; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
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