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J. Biol. Chem., Vol. 282, Issue 50, 36155-36166, December 14, 2007

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Sumoylation-dependent Control of Homotypic and Heterotypic Synergy by the Krüppel-type Zinc Finger Protein ZBP-89^*

Sergey Chupreta, Holly Brevig, Longchuan Bai, Juanita L. Merchant^¶, and Jorge A. Iñiguez-Lluhí¹

From the Departments of Pharmacology, Internal Medicine, and ^¶Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632

The Krüppel-like transcription factor ZBP-89 is a sequence-specific regulator that plays key roles in cellular growth and differentiation especially in endodermal and germ cell lineages. ZBP-89 shares with other members of the Sp-like family an overlapping sequence specificity for GC-rich sequences in the regulatory regions of multiple genes. Defining the mechanisms that govern the intrinsic function of ZBP-89 as well as its competitive and non-competitive functional interactions with other regulators is central to understand how ZBP-89 exerts its biological functions. We now describe that post-translational modification of ZBP-89 by multiple small ubiquitin-like modifier (SUMO) isoforms occurs at two conserved synergy control motifs flanking the DNA binding domain. Functionally sumoylation did not directly alter the ability of ZBP-89 to compete with other Sp-like factors from individual sites. At promoters bearing multiple response elements, however, this modification inhibited the functional cooperation between ZBP-89 and Sp1. Analysis of the properties of ZBP-89 in cellular contexts devoid of competing factors indicated that although on its own it behaves as a modest activator it potently synergizes with heterologous activators such as the glucocorticoid receptor. Notably we found that when conjugated to ZBP-89, SUMO exerts a strong inhibitory effect on such synergistic interactions through a critical conserved functional surface. By regulating higher order functional interactions, sumoylation provides a reversible post-translational mechanism to control the activity of ZBP-89.

Received for publication, October 1, 2007

^* This work was supported by United States Public Health Service Grants DK61656-01 and P60 DK20572 (to J. A. I.), T32 GM007767 (to H. B.), and R01 DK55732 (to J. L. M.). 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. 1.

¹ To whom correspondence should be addressed. Tel.: 734-615-6565; Fax: 734-763-4450; E-mail: iniguez{at}umich.edu.

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