AML1/RUNX1 phosphorylation by cyclin-dependent kinases regulates the degradation of AML1/RUNX1 by the anaphase-promoting complex
AML1/RUNX1 phosphorylation by cyclin-dependent kinases regulates the degradation of AML1/RUNX1 by the anaphase-promoting complex
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DOI：
10.1128/mcb.00597-06
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发表时间：
2006-10-01
影响因子：
5.3
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
--
作者：
Biggs, Joseph R.;Peterson, Luke F.;Zhang, Dong-Er
AML 1（RUNX 1）调节造血、血管生成、肌肉功能和神经发生。以前的研究表明，AML 1的磷酸化，特别是在丝氨酸276和303，影响其转录激活。在这里，我们报告，AML 1丝氨酸276和303的磷酸化可以在体内被细胞周期蛋白依赖性激酶（CDKs）Cdk 1和Cdk 2的抑制剂阻断。此外，这些残基可以在体外被纯化的Cdk 1/细胞周期蛋白B和Cdk 2/细胞周期蛋白A磷酸化。不能在这些位点磷酸化的突变型AML 1蛋白（AML 14 A）比野生型AMLL更稳定。AML-4A对由Cdc 20介导的降解具有抗性，Cdc 20是后期促进复合物（APQ）的底物靶向亚基之一。然而，APC使用的另一个靶向亚基Cdhl可以介导AML 14 A的降解。磷酸化模拟蛋白AML 14 D可以被Cdc 20或Cdh 1靶向。这些观察结果表明，Cdc 20和Cdhl都可以靶向AMLI以通过APC降解，但是AMLI磷酸化可能在更大程度上影响Cdc 20-APC介导的降解。
AML1 (RUNX1) regulates hematopoiesis, angiogenesis, muscle function, and neurogenesis. Previous studies have shown that phosphorylation of AML1, particularly at serines 276 and 303, affects its transcriptional activation. Here, we report that phosphorylation of AML1 serines 276 and 303 can be blocked in vivo by inhibitors of the cyclin-dependent kinases (CDKs) Cdkl and Cdk2. Furthermore, these residues can be phosphorylated in vitro by purified Cdkl/cyclin B and Cdk2/cyclin A. Mutant AML1 protein which cannot be phosphorylated at these sites (AML14A) is more stable than wild-type AMLL AML-4A is resistant to degradation mediated by Cdc20, one of the substrate-targeting subunits of the anaphase-promoting complex (APQ. However, Cdhl, another targeting subunit used by the APC, can mediate the degradation of AML14A. A phospho-mimic protein, AML14D, can be targeted by Cdc20 or Cdh1. These observations suggest that both Cdc20 and Cdhl can target AMLI for degradation by the APC but that AMLI phosphorylation may affect degradation mediated by Cdc20-APC to a greater degree.