Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1

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Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1. / Jang, Sung-Wuk; Yang, Seung-ju; Ehlén, Åsa; Dong, Shaozhong; Khoury, Hanna; Chen, Jing; Persson, Jenny L; Ye, Keqiang.

I: Cancer Research, Vol. 68, Nr. 12, 2008, s. 4559-4570.

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Jang, Sung-Wuk ; Yang, Seung-ju ; Ehlén, Åsa ; Dong, Shaozhong ; Khoury, Hanna ; Chen, Jing ; Persson, Jenny L ; Ye, Keqiang. / Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1. I: Cancer Research. 2008 ; Vol. 68, Nr. 12. s. 4559-4570.

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TY - JOUR

T1 - Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1

AU - Jang, Sung-Wuk

AU - Yang, Seung-ju

AU - Ehlén, Åsa

AU - Dong, Shaozhong

AU - Khoury, Hanna

AU - Chen, Jing

AU - Persson, Jenny L

AU - Ye, Keqiang

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1158/0008-5472.CAN-08-0021

DO - 10.1158/0008-5472.CAN-08-0021

M3 - Article

VL - 68

SP - 4559

EP - 4570

JO - Cancer research. Supplement

JF - Cancer research. Supplement

SN - 1538-7445

IS - 12

ER -