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

Title: Identification of the oncogenic kinase TOPK/PBK as a master mitotic regulator of C2H2 zinc finger proteins.
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Name(s): Rizkallah, Raed, author
Batsomboon, Paratchata, author
Dudley, Gregory B, author
Hurt, Myra M, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2015-01-30
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_pmch_25575812 (IID), 10.18632/oncotarget.2735 (DOI), PMC4359306 (PMCID), 25575812 (RID), 25575812 (EID), 2735 (PII)
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359306.
Subject(s): Carbazoles/pharmacology
Carrier Proteins/antagonists & inhibitors
Carrier Proteins/genetics
Carrier Proteins/metabolism
Cell Line, Tumor
Gene Knockdown Techniques
HeLa Cells
Humans
Indole Alkaloids/pharmacology
Mitogen-Activated Protein Kinase Kinases/genetics
Mitogen-Activated Protein Kinase Kinases/metabolism
Mitosis/physiology
Nuclear Proteins/antagonists & inhibitors
Nuclear Proteins/genetics
Nuclear Proteins/metabolism
Phosphorylation
Protein Kinase Inhibitors/pharmacology
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_25575812
Owner Institution: FSU
Is Part Of: Oncotarget.
1949-2553
Issue: iss. 3, vol. 6

Choose the citation style.
Rizkallah, R., Batsomboon, P., Dudley, G. B., & Hurt, M. M. (2015). Identification of the oncogenic kinase TOPK/PBK as a master mitotic regulator of C2H2 zinc finger proteins. Oncotarget. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_25575812