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World J Biol Chem. Jun 26, 2011; 2(6): 126-131
Published online Jun 26, 2011. doi: 10.4331/wjbc.v2.i6.126
Regulation of Ikaros function by casein kinase 2 and protein phosphatase 1
Chunhua Song, Zhanjun Li, Amy K Erbe, Aleksandar Savic, Sinisa Dovat
Chunhua Song, Zhanjun Li, Sinisa Dovat, Department of Pediatrics, Pennsylvania State University, College of Medicine, Hershey, PA 17033-0850, United States
Amy K Erbe, Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53792, United States
Aleksandar Savic, Clinic of Hematology, Clinical Center of Vojvodina, Faculty of Medicine, University in Novi Sad, Novi Sad, 21000, Serbia
Author contributions: Song C, Li Z and Savic A performed the bibliographical review of the literature; Erbe AK and Song C were responsible for critically reviewing and revising the manuscript; Dovat S prepared the initial draft of the manuscript and edited it for final revisions.
Supported by (in part) An NIH R01 HL095120 grant, a St. Baldrick’s Foundation Career Development Award, the Four Diamonds Fund of the Pennsylvania State University College of Medicine, and the John Wawrynovic Leukemia Research Scholar Endowment (SD)
Correspondence to: Sinisa Dovat, MD, PhD, Associate Professor of Pediatrics, Four Diamonds Endowed Chair, Department of Pediatrics, Pennsylvania State University, College of Medicine, H085, Division of Pediatric Hematology/Oncology, 500 University Drive, PO Box 850, Hershey, PA 17033-0850, United States. sdovat@hmc.psu.edu
Telephone: +1-717-5310003 Fax: +1-717-5314789
Received: March 22, 2011
Revised: April 29, 2011
Accepted: May 6, 2011
Published online: June 26, 2011
Abstract

The Ikaros gene encodes a zinc finger, DNA-binding protein that regulates gene transcription and chromatin remodeling. Ikaros is a master regulator of hematopoiesis and an established tumor suppressor. Moderate alteration of Ikaros activity (e.g. haploinsufficiency) appears to be sufficient to promote malignant transformation in human hematopoietic cells. This raises questions about the mechanisms that normally regulate Ikaros function and the potential of these mechanisms to contribute to the development of leukemia. The focus of this review is the regulation of Ikaros function by phosphorylation/dephosphorylation. Site-specific phosphorylation of Ikaros by casein kinase 2 (CK2) controls Ikaros DNA-binding ability and subcellular localization. As a consequence, the ability of Ikaros to regulate cell cycle progression, chromatin remodeling, target gene expression, and thymocyte differentiation are controlled by CK2. In addition, hyperphosphorylation of Ikaros by CK2 leads to decreased Ikaros levels due to ubiquitin-mediated degradation. Dephosphorylation of Ikaros by protein phosphatase 1 (PP1) acts in opposition to CK2 to increase Ikaros stability and restore Ikaros DNA binding ability and pericentromeric localization. Thus, the CK2 and PP1 pathways act in concert to regulate Ikaros activity in hematopoiesis and as a tumor suppressor. This highlights the importance of these signal transduction pathways as potential mediators of leukemogenesis via their role in regulating the activities of Ikaros.

Keywords: Ikaros; Leukemia; Zinc finger; Transcription factor; Casein kinase 2; Protein phosphatase 1; Phosphorylation