Ikaros, CK2 kinase, and the road to leukemia.
Ikaros, CK2 kinase, and the road to leukemia.
复制标题
DOI：
10.1007/s11010-011-0964-5
复制
发表时间：
2011-10
影响因子：
4.3
通讯作者：
Li, Zhanjun
中科院分区：
文献类型：
--
作者：
Dovat, Sinisa;Song, Chunhua;Payne, Kimberly J.;Li, Zhanjun
关键词：
Ikaros编码一种锌指蛋白，它对造血至关重要，在白血病中起肿瘤抑制作用。Ikaros的功能取决于其定位于近着丝粒异染色质（PC-HC）的能力。Ikaros蛋白与靶基因的上游调控元件结合，帮助其募集到PC-HC，并通过染色质重塑调节其转录。我们确定了四个新的Ikaros磷酸化位点，被CK 2激酶磷酸化。利用Ikaros磷酸化模拟物和磷酸化抗性突变体的CK 2磷酸化位点，我们证明：1）CK 2介导的磷酸化抑制Ikaros在PC-HC上的定位; 2）CK 2位点的Ikaros去磷酸化增加了其与末端脱氧核苷酸转移酶（TdT）基因启动子的结合，导致胸腺细胞分化期间TdT抑制，3）Ikaros的过度磷酸化通过泛素/蛋白酶体途径促进其降解。我们发现，Ikaros是通过蛋白磷酸酶1（PP 1）通过在一个共识PP 1结合基序，RVXF相互作用去磷酸化。取消Ikaros-PP 1相互作用的点突变导致DNA结合亲和力和亚细胞定位的功能变化，类似于在过度磷酸化的Ikaros和/或Ikaros磷酸模拟突变体中观察到的那些。CK 2位点的磷酸盐抗性Ikaros突变恢复了Ikaros的DNA结合活性和定位于PC-HC，并阻止了Ikaros的加速降解。结果表明CK 2激酶在淋巴细胞分化和调节Ikaros功能中的作用，并表明CK 2通过抑制Ikaros的肿瘤抑制活性促进白血病发生。我们提出了一个模型，其中CK 2激酶和PP 1磷酸酶的平衡对于正常淋巴细胞分化和预防恶性转化至关重要。
Ikaros encodes a zinc finger protein that is essential for hematopoiesis and that acts as a tumor suppressor in leukemia. Ikaros function depends on its ability to localize to pericentromeric heterochromatin (PC-HC). Ikaros protein binds to the upstream regulatory elements of target genes, aids in their recruitment to PC-HC, and regulates their transcription via chromatin remodeling. We identified four novel Ikaros phosphorylation sites that are phosphorylated by CK2 kinase. Using Ikaros phosphomimetic and phosphoresistant mutants of the CK2 phosphorylation sites we demonstrate that: 1) CK2-mediated phosphorylation inhibits Ikaros’ localization to PC-HC; 2) dephosphorylation of Ikaros at CK2 sites increases its binding to the promoter of the terminal deoxynucleotidetransferase (TdT) gene leading to TdT repression during thymocyte differentiation, and 3) hyperphosphorylation of Ikaros promotes its degradation by the ubiquitin/proteasome pathway. We show that Ikaros is dephosphorylated by Protein Phosphatase 1 (PP1) via interaction at a consensus PP1-binding motif, RVXF. Point mutations that abolish Ikaros-PP1 interaction result in functional changes in DNA-binding affinity and subcellular localization similar to those observed in hyperphosphorylated Ikaros and/or Ikaros phosphomimetic mutants. Phosphoresistant Ikaros mutations at CK2 sites restored Ikaros’ DNA-binding activity and localization to PC-HC and prevented accelerated Ikaros degradation. Results demonstrate the role of CK2 kinase in lymphocyte differentiation and in regulation of Ikaros’ function, and suggest that CK2 promotes leukemogenesis by inhibiting the tumor suppressor activity of Ikaros. We propose a model whereby the balance of CK2 kinase and PP1 phosphatase is essential for normal lymphocyte differentiation and for the prevention of malignant transformation.
登录
查看更多内容
影响因子：
5.3
作者：
MOLNAR, A;GEORGOPOULOS, K
通讯作者：
GEORGOPOULOS, K
影响因子：
5.3
作者：
Kathrein, KL;Lorenz, R;Winandy, S
通讯作者：
Winandy, S
影响因子：
64.8
作者：
Mullighan, Charles G.;Goorha, Salil;Downing, James R.
通讯作者：
Downing, James R.
影响因子：
7
作者：
Kim, Jung-Hyun;Ebersole, Thomas;Larionov, Vladimir
通讯作者：
Larionov, Vladimir
影响因子：
4.8
作者：
Koipally, J;Georgopoulos, K
通讯作者：
Georgopoulos, K