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Serine/Arginine Protein–Specific Kinase 2 Promotes Leukemia Cell Proliferation by Phosphorylating Acinus and Regulating Cyclin A1

¹ Department of Pathology and Laboratory Medicine and ² Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia; and ³ Division of Pathology, Department of Laboratory Medicine, Lund University, University Hospital, Malmö, Sweden

Requests for reprints: Keqiang Ye, Emory University, Room 145, Whitehead Building, 615 Michael Street, Atlanta, GA 30322. Phone: 404-712-2814; Fax: 404-712-2979; E-mail: kye{at}emory.edu.

Key Words: SRPK2 • acinus • cyclin A1 • phosphorylation • cell proliferation

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 G₁ 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. [Cancer Res 2008;68(12):4559–70]