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

Yan Liu, Cyrus V. Hedvat, Shifeng Mao, Xin Hua Zhu, Jinjuan Yao, Hoang Nguyen, Andrew Koff, Stephen D. Nimer

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 α 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 G1 phase of the cell cycle; we now show that MEF is a short-lived protein whose expression level also peaks during late G1 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 SCFSkp2, which targets MEF for ubiquitination and proteolysis. Overexpression of MEF drives cells through the G1/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.

Original languageEnglish (US)
Pages (from-to)3114-3123
Number of pages10
JournalMolecular and Cellular Biology
Volume26
Issue number8
DOIs
StatePublished - Apr 2006
Externally publishedYes

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Ubiquitin-Protein Ligases
Proteolysis
Cell Cycle
Phosphorylation
G1 Phase
Natural Killer Cells
Transcription Factors
Cell Proliferation
Cyclin A
Retinoic Acid Receptors
Proteins
Ubiquitination
Threonine
Hematopoietic Stem Cells
S Phase
Mutagenesis
Serine
Leukemia
T-Lymphocytes
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

The ETS protein MEF is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCFSkp2. / Liu, Yan; Hedvat, Cyrus V.; Mao, Shifeng; Zhu, Xin Hua; Yao, Jinjuan; Nguyen, Hoang; Koff, Andrew; Nimer, Stephen D.

In: Molecular and Cellular Biology, Vol. 26, No. 8, 04.2006, p. 3114-3123.

Research output: Contribution to journalArticle

Liu, Yan ; Hedvat, Cyrus V. ; Mao, Shifeng ; Zhu, Xin Hua ; Yao, Jinjuan ; Nguyen, Hoang ; Koff, Andrew ; Nimer, Stephen D. / The ETS protein MEF is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCFSkp2. In: Molecular and Cellular Biology. 2006 ; Vol. 26, No. 8. pp. 3114-3123.
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