The ETS protein MEF is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCFSkp2
The ETS protein MEF is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCFSkp2
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DOI：
10.1128/mcb.26.8.3114-3123.2006
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发表时间：
2006-04-01
影响因子：
5.3
通讯作者：
Nimer, SD
中科院分区：
文献类型：
--
作者：
Liu, Y;Hedvat, CV;Nimer, SD
MEF是一种与ets相关的转录因子，具有较强的转录激活活性，影响造血干细胞的行为，是正常NK细胞和NK t细胞发育所必需的。MEF（也被称为ELF4）基因被几种白血病相关的融合转录因子蛋白（pml -维甲酸受体α和AML1-ETO）抑制，但在几种癌症模型中，它也被逆转录病毒插入激活。我们之前的研究表明，细胞周期蛋白a依赖性的MEF磷酸化在很大程度上限制了其活性在细胞周期的G期；我们现在发现MEF是一种短寿命蛋白，其表达水平也在G期晚期达到峰值。诱变研究表明，MEF在S期的快速周转依赖于cdk2对MEF C端苏氨酸643和丝氨酸648的特异性磷酸化，以及Skp1/Cul1/F-box (SCF) E3泛素连接酶复合物SCFSkp2的磷酸化，该复合物靶向MEF泛素化和蛋白水解。MEF的过表达驱动细胞通过G(1)/S转变，从而促进细胞增殖。MEF水平在细胞周期中受到严格调控，从而起到调控细胞周期进入和细胞增殖的作用。
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.