MEF/ELF4 transactivation by E2F1 is inhibited by p53.
Myeloid elf-1-like factor (MEF) or Elf4 is an E-twenty-six (ETS)-related transcription factor with strong transcriptional activity that influences cellular senescence by affecting tumor suppressor p53. MEF downregulates p53 expression and inhibits p53-mediated cellular senescence by transcriptionally activating MDM2. However, whether p53 reciprocally opposes MEF remains unexplored. Here, we show that MEF is modulated by p53 in human cells and mice tissues. MEF expression and promoter activity were suppressed by p53. While we found that MEF promoter does not contain p53 response elements, intriguingly, it contains E2F consensus sites. Subsequently, we determined that E2F1 specifically binds to MEF promoter and transactivates MEF. Nevertheless, E2F1 DNA binding and transactivation of MEF promoter was inhibited by p53 through the association between p53 and E2F1. Furthermore, we showed that activation of p53 in doxorubicin-induced senescent cells increased E2F1 and p53 interaction, diminished E2F1 recruitment to MEF promoter and reduced MEF expression. These observations suggest that p53 downregulates MEF by associating with and inhibiting the binding activity of E2F1, a novel transcriptional activator of MEF. Together with previous findings, our present results indicate that a negative regulatory mechanism exists between p53 and MEF.
Taura
Manabu
M
Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE 'Cell Fate Regulation Research and Education Unit', Kumamoto University, Kumamoto 862-0973, Japan.
Suico
Mary Ann
MA
Fukuda
Ryosuke
R
Koga
Tomoaki
T
Shuto
Tsuyoshi
T
Sato
Takashi
T
Morino-Koga
Saori
S
Okada
Seiji
S
Kai
Hirofumi
H
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C111931:ELF4 protein, human; C491779:Elf4 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
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