Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating acinus and regulating cyclin A1.
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(1) 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.
Department of Pathology and Laboratory Medicine and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
Sung-Wuk
SW
Jang
Seung-Ju
SJ
Yang
Asa
A
Ehlén
Shaozhong
S
Dong
Hanna
H
Khoury
Jing
J
Chen
Jenny L
JL
Persson
Keqiang
K
Ye
D001853:Bone Marrow / Q000378:metabolism; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism*; D056750:Cyclin A1; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007938:Leukemia / Q000201:enzymology* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt; D012441:Saccharomyces cerevisiae; D012694:Serine / Q000737:chemistry / Q000235:genetics; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques
C121310:ACIN1 protein, human; C503745:CCNA1 protein, human; D019925:Cyclin A; D056750:Cyclin A1; D009687:Nuclear Proteins; D012694:Serine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C110522:SRPK2 protein, human