Oncotarget

Research Papers:

Identification of the oncogenic kinase TOPK/PBK as a master mitotic regulator of C2H2 zinc finger proteins

Raed Rizkallah _, Paratchata Batsomboon, Gregory B. Dudley and Myra M. Hurt

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Oncotarget. 2015; 6:1446-1461. https://doi.org/10.18632/oncotarget.2735

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Abstract

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

Correspondence to:

Raed Rizkallah, e-mail: raed.rizkallah@med.fsu.edu

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

ABSTRACT

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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