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J. Biol. Chem., Vol. 282, Issue 4, 2538-2547, January 26, 2007

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Human Ikaros Function in Activated T Cells Is Regulated by Coordinated Expression of Its Largest Isoforms^*

Tapani Ronni, Kimberly J. Payne, Sam Ho^¶, Michelle N. Bradley^||, Glenn Dorsam^**, and Sinisa Dovat^¶1

From the Mattel Children's Hospital and the ^||Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095, the Childrens Hospital Los Angeles, California 90027, the ^¶Department of Pediatrics, University of Wisconsin, Madison, Wisconsin 53792, and the ^**Department of Chemistry and Molecular Biology, North Dakota State University, Fargo, North Dakota 58105

The Ikaros gene is alternately spliced to generate multiple zinc finger proteins involved in gene regulation and chromatin remodeling. Whereas murine studies have provided important information regarding the role of Ikaros in the mouse, little is known of Ikaros function in human. We report functional analyses of the two largest human Ikaros (hIK) isoforms, hIK-VI and hIK-H, in T cells. Abundant expression of hIK-H, the largest described isoform, is restricted to human hematopoietic cells. We find that the DNA binding affinity of hIK-H differs from that of hIK-VI. Co-expression of hIk-H with hIk-VI alters the ability of Ikaros complexes to bind DNA motifs found in pericentromeric heterochromatin (PC-HC). In the nucleus, hIK-VI is localized solely in PC-HC, whereas the hIK-H protein exhibits dual centromeric and non-centromeric localization. Mutational analysis defined the amino acids responsible for the distinct DNA binding ability of hIK-H, as well as the sequence required for the specific subcellular localization of this isoform. In proliferating cells, the binding of hIK-H to the upstream regulatory region of known Ikaros target genes correlates with their positive regulation by Ikaros. Results suggest that expression of hIK-H protein restricts affinity of Ikaros protein complexes toward specific PC-HC repeats. We propose a model, whereby the binding of hIK-H-deficient Ikaros complexes to the regulatory sequence of target genes would recruit these genes to the restrictive pericentromeric compartment, resulting in their repression. The presence of hIK-H in the Ikaros complex would alter its affinity for PC-HC, leading to chromatin remodeling and activation of target genes.

Received for publication, June 12, 2006 , and in revised form, October 24, 2006.

^* This work was supported in part by National Institutes of Health Grants: K22 CA 111392 (to S. D.), 1F32DK10101, 5K01 DK066163 (to K. J. P.), a Research Career Development Award from the Saban Research Institute at Childrens Hospital, Los Angeles (to K. J. P.), grants from the Howard Hughes Medical Institute (HHMI) at UCLA (to M. N. B.), a Midwest Athletes Against Childhood Cancer (MACC) Grant Award, and a Cure Kids Cancer Coalition (CKCC) Grant (to S. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: University of Wisconsin, Dept. of Pediatrics, Division of Pediatric Hematology/Oncology, 600 Highland Ave, H4/431 CSC, Madison, WI 53792-4108. Tel.: 608-262-2415; Fax: 608-265-9721; E-mail: dovat{at}wisc.edu.

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				Z. Gurel, T. Ronni, S. Ho, J. Kuchar, K. J. Payne, C. W. Turk, and S. Dovat Recruitment of Ikaros to Pericentromeric Heterochromatin Is Regulated by Phosphorylation J. Biol. Chem., March 28, 2008; 283(13): 8291 - 8300. [Abstract] [Full Text] [PDF]