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.
Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 575, New York, NY 10021, USA.
Yan
Y
Liu
Cyrus V
CV
Hedvat
Shifeng
S
Mao
Xin-Hua
XH
Zhu
Jinjuan
J
Yao
Hoang
H
Nguyen
Andrew
A
Koff
Stephen D
SD
Nimer
D000595:Amino Acid Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D007976:Leupeptins / Q000494:pharmacology; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D025801:Ubiquitin / Q000032:analysis / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; C111931:ELF4 protein, human; D007976:Leupeptins; D011506:Proteins; D014157:Transcription Factors; D025801:Ubiquitin; D013912:Threonine; D012694:Serine; D008025:Ligases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde