SRPK2 Promotes Leukemia Cell Proliferation by Phosphorylating Acinus and Regulating Cyclin A1

• Type of Material: Article
• Authors: Sung-Wuk Jang, Emory University; Seung-ju Yang, Emory University; Asa Ehlen, Lund University; Shaozhong Dong, Emory University; H Jean Khoury, Emory University; Jing Chen, Emory University; Jenny L. Persson, Lund University; Keqiang Ye, Emory University
• Language: English
• Date: 2008-06-15
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2008 American Association for Cancer Research
• Final Published Version (URL): http://cancerres.aacrjournals.org/content/68/12/4559
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 68
• Issue: 12
• Start Page: 4559
• End Page: 4570
• Grant/Funding Information: National Institute of Neurological Disorders and Stroke : NINDS; This work is supported by grants from National Institute of Health (RO1, NS045627) to K. Ye.
• Keywords: SRPK2; Acinus; Cyclin A1; Cell proliferation; Phosphorylation
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

SRPK, a family of cell cycle regulated protein kinases, phosphorylate Serine/Arginine (SR) domain-containing proteins in nuclear speckles and mediate the pre-mRNA splicing. However, the physiological 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 upregulation. 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. Further, both SRPK2 and acinus are overexpressed in some of human AML 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.