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The ETS protein MEF is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCFSkp2.

MEF is an ETS-related transcription factor with strong transcriptional activating activity that affects hematopoietic stem cell behavior and is required for normal NK cell and NK T-cell development. The MEF (also known as ELF4) gene is repressed by several leukemia-associated fusion transcription factor proteins (PML-retinoic acid receptor alpha and AML1-ETO), but it is also activated by retroviral insertion in several cancer models. We have previously shown that cyclin A-dependent phosphorylation of MEF largely restricts its activity to the G(1) phase of the cell cycle; we now show that MEF is a short-lived protein whose expression level also peaks during late G(1) phase. Mutagenesis studies show that the rapid turnover of MEF in S phase is dependent on the specific phosphorylation of threonine 643 and serine 648 at the C terminus of MEF by cdk2 and on the Skp1/Cul1/F-box (SCF) E3 ubiquitin ligase complex SCF(Skp2), which targets MEF for ubiquitination and proteolysis. Overexpression of MEF drives cells through the G(1)/S transition, thereby promoting cell proliferation. The tight regulation of MEF levels during the cell cycle contributes to its effects on regulating cell cycle entry and cell proliferation.

Pubmed ID: 16581786

Authors

  • Liu Y
  • Hedvat CV
  • Mao S
  • Zhu XH
  • Yao J
  • Nguyen H
  • Koff A
  • Nimer SD

Journal

Molecular and cellular biology

Publication Data

April 3, 2006

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK 52208
  • Agency: NIGMS NIH HHS, Id: GM 52597
  • Agency: NHLBI NIH HHS, Id: K08 HL 04478

Mesh Terms

  • Amino Acid Sequence
  • Cell Line
  • Cell Line, Tumor
  • Cysteine Proteinase Inhibitors
  • DNA-Binding Proteins
  • Gene Expression Regulation
  • Half-Life
  • Humans
  • Hydrolysis
  • Leupeptins
  • Ligases
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Proteins
  • Serine
  • Threonine
  • Transcription Factors
  • Ubiquitin