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.
Liu
Yan
Y
Division of Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 575, New York, NY 10021, USA.
Hedvat
Cyrus V
CV
Mao
Shifeng
S
Zhu
Xin-Hua
XH
Yao
Jinjuan
J
Nguyen
Hoang
H
Koff
Andrew
A
Nimer
Stephen D
SD
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