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
Pages (from-to)3114-3123
Number of pages10
JournalMolecular and Cellular Biology
Volume26
Issue number8
DOIs
StatePublished - Apr 1 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, 01.04.2006, 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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