title: The transcription factor MEF/Elf4 is dually modulated by p53-MDM2 axis and MEF-MDM2 autoregulatory mechanism.
abstract: Myeloid Elf-1-like factor (MEF) or Elf4 is an ETS transcription factor that activates innate immunity-associated genes such as lysozyme (LYZ), human β-defensin 2 (HβD2), and interleukin-8 (IL-8) in epithelial cells and is also known to influence cell cycle progression. MEF is transcriptionally activated by E2F1, but the E2F1-mediated transcriptional activation is inhibited by p53 through E2F1-p53 protein interaction. Although the transcriptional activation of MEF has been investigated in depth, its post-translational regulation is not well explored. By overexpressing MEF cDNA in human cell lines, here we show that MEF protein expression is suppressed by p53. By screening a number of E3 ligases regulated by p53, we found that MDM2 is involved in the effect of p53 on MEF. MDM2 is transcriptionally activated by p53 and interacts with MEF protein to enhance MEF degradation. MDM2 reduces MEF protein expression, as well as stability and function of MEF as transcriptional activator. Furthermore, MDM2 was able to down-regulate MEF in the absence of p53, indicating a p53-independent effect on MEF. Notably, MEF transcriptionally activates MDM2, which was previously demonstrated to be the mechanism by which MEF suppresses the p53 protein. These results reveal that in addition to the potential of MEF to down-regulate p53 by transcriptionally activating E3 ligase MDM2, MEF participates with MDM2 in a novel autoregulatory feedback loop to regulate itself. Taken together with the findings on the effect of p53 on MEF, these data provide evidence that the p53-MDM2-MEF axis is a feedback mechanism that exquisitely controls the balance of these transcriptional regulators.
authors: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: mann@gpo.kumamoto-u.ac.jp.
authors: Mary Ann
authors: MA
authors: Suico
authors: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors: Ryosuke
authors: R
authors: Fukuda
authors: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors: Rui
authors: R
authors: Miyakita
authors: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors: Kosuke
authors: K
authors: Koyama
authors: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors: Manabu
authors: M
authors: Taura
authors: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors: Tsuyoshi
authors: T
authors: Shuto
authors: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors: Hirofumi
authors: H
authors: Kai
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D025461:Feedback, Physiological; D015870:Gene Expression; D045325:HCT116 Cells; D006801:Humans; D055550:Protein Stability; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: ETS Transcription Factor Family; Mouse Double Minute 2 Homolog (MDM2); Myeloid Elf-1-like Factor/Elf-4; Protein Degradation; Transcription Factor; p53