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

被引:32
作者
Liu, Y
Hedvat, CV
Mao, SF
Zhu, XH
Yao, JJ
Nguyen, H
Koff, A
Nimer, SD
机构
[1] Mem Sloan Kettering Canc Ctr, Dept Med, Div Hematol Oncol, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Lab Mol Aspects Hematopoiesis, New York, NY 10021 USA
[3] Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA
[4] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, New York, NY 10021 USA
[5] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA
关键词
D O I
10.1128/MCB.26.8.3114-3123.2006
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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, phase of the cell cycle; we now show that MEF is a short-lived protein whose expression level also peaks during late G, 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 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.
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收藏
页码:3114 / 3123
页数:10
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