Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1
Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1
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DOI：
10.1158/0008-5472.can-08-0021
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发表时间：
2008-06-15
期刊：
影响因子：
11.2
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Jang, Sung-Wuk;Yang, Seung-ju;Ye, Keqiang
丝氨酸/精氨酸（SR）蛋白特异性激酶（SRPK）是一类细胞周期调节蛋白激酶，可磷酸化核斑点中含有SR结构域的蛋白并介导mrna前剪接。然而，这一事件在细胞周期中的生理作用尚不完全清楚。在这里，我们发现SRPK2结合并磷酸化acinus，这是RNA剪接所必需的SR蛋白，并将其从核斑点重新分配到核质中，导致细胞周期蛋白A1而不是A2上调。Acinus S422D是一种SRPK2磷酸化模拟物，可以增强细胞周期蛋白A1的转录，而Acinus S422A是一种不可磷酸化的突变体，可以阻断SRPK2的刺激作用。消融腺泡或SRPK2可消除白血病细胞中cyclin A1的表达，使细胞停留在G期。acinus或SRPK2的过表达会增加白血病细胞的增殖。此外，SRPK2和acinus在一些人类急性髓性白血病患者中均过表达，并与细胞周期蛋白A1表达水平升高相关，这与细胞周期蛋白A1在白血病中的致癌活性相吻合。因此，我们的研究结果建立了SR剪接机制调控细胞周期并参与白血病肿瘤发生的分子机制。
Serine/arginine (SR) protein-specific kinase (SRPK), a family of cell cycle-regulated protein kinases, phosphorylate SR domain-containing proteins in nuclear speckles and mediate the pre-mRNA splicing. However, the physiologic roles of this event in cell cycle are incompletely understood. Here, we show that SRPK2 binds and phosphorylates acinus, an SR protein essential for RNA splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not A2 up-regulation. Acinus S422D, an SRPK2 phosphorylation mimetic, enhances cyclin A1 transcription, whereas acinus S422A, an unphosphorylatable mutant, blocks the stimulatory effect of SRPK2. Ablation of acinus or SRPK2 abrogates cyclin A1 expression in leukemia cells and arrest cells at G, phase. Overexpression of acinus or SRPK2 increases leukemia cell proliferation. Furthermore, both SRPK2 and acinus are overexpressed in some human acute myelogenous leukemia patients and correlate with elevated cyclin A1 expression levels, fitting with the oncogenic activity of cyclin A1 in leukemia. Thus, our findings establish a molecular mechanism by which SR splicing machinery regulates cell cycle and contributes to leukemia tumorigenesis.