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J. Biol. Chem., Vol. 283, Issue 34, 23235-23243, August 22, 2008

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Regulation of Cardiac Specific nkx2.5 Gene Activity by Small Ubiquitin-like Modifier^*

Jun Wang¹, Hua Zhang, Dinakar Iyer, Xin-Hua Feng^¶, and Robert J. Schwartz

From the Institute of Biosciences and Technology, Texas A & M Health Science Center, Houston, Texas 77030 and the Departments of Medicine and ^¶Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

The cardiac specific homeobox gene nkx2.5, a member of the nk-2 class family, plays a central role in cardiogenesis and is a target of the small ubiquitin-like modifier (SUMO). Nkx2.5 was modified by SUMO on its 51st amino acid, a lysine residue conserved across species but absent in other nk-2 members. Conversion of this lysine to an arginine (K51R) substantially reduced Nkx2.5 DNA binding and also its transcriptional activity. Unexpectedly, mutant K51R was targeted by ubiquitin. E3 ligase PIAS proteins PIAS1, PIASx, and PIASy, but not PIAS3, enhanced SUMO-1 attachment to Nkx2.5 on the primary SUMO acceptor site. SUMO-2 linkage to Nkx2.5 was catalyzed only by PIASx and not by other PIAS proteins. SUMO conjugation stabilized the formation of Nkx2.5-containing complexes that led to robust transcriptional activation. Thus, SUMO modification serves as a positive regulator for Nkx2.5 transcriptional activity.

Received for publication, November 29, 2007 , and in revised form, June 18, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health grants (to R. J. S. and X. H. F.). This work was also supported by funding from the Texas A&M Health Science Center (to J. W.). 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.

¹ To whom correspondence should be addressed: 2121 W. Holcombe Blvd., Houston, TX 77030. Fax: 713-677-7779; E-mail: junwang{at}ibt.tamhsc.edu.

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