Identification of the oncogenic kinase TOPK/PBK as a master mitotic regulator of C2H2 zinc finger proteins
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Raed Rizkallah1, Paratchata Batsomboon2, Gregory B. Dudley2, Myra M. Hurt1
1Department of Biomedical Sciences, Florida State University, Tallahassee, Florida, 32306, United States of America
2Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, 32306, United States of America
Raed Rizkallah, e-mail: [email protected]
Keywords: Kinase, Mitosis, Phosphorylation, Zinc Finger Proteins, TOPK/PBK
Abbreviation: ZFP: Zinc Finger Protein
Received: August 26, 2014 Accepted: November 08, 2014 Published: January 13, 2015
TOPK/PBK is an oncogenic kinase upregulated in most human cancers and its high expression correlates with poor prognosis. TOPK is known to be activated by Cdk1 and needed for mitotic cell division; however, its mitotic functions are not yet fully understood. In this study, we show that TOPK plays a global mitotic role by simultaneously regulating hundreds of DNA binding proteins. C2H2 zinc finger proteins (ZFPs) constitute the largest family of human proteins. All C2H2 ZFPs contain a highly conserved linker sequence joining their multi-zinc finger domains. We have previously shown that phosphorylation of this conserved motif serves as a global mechanism for the coordinate dissociation of C2H2 ZFPs from condensing chromatin, during mitosis. Here, using a panel of kinase inhibitors, we identified K252a as a potent inhibitor of mitotic ZFP linker phosphorylation. We generated a biotinylated form of K252a and used it to purify candidate kinases. From these candidates we identified TOPK/PBK, in vitro and in vivo, as the master ZFP linker kinase. Furthermore, we show precise temporal correlation between TOPK activating phosphorylation by Cdk1 and linker phosphorylation in mitosis. The identification of this fundamental role of TOPK underscores its significance as a promising novel target of cancer therapeutics.
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