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J. Biol. Chem., Vol. 281, Issue 24, 16664-16671, June 16, 2006

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Sumoylation Delimits KLF8 Transcriptional Activity Associated with the Cell Cycle Regulation^*

Huijun Wei, Xianhui Wang, Boyi Gan, Alison M. Urvalek, Zara K. Melkoumian, Jun-Lin Guan, and Jihe Zhao¹

From the Department of Molecular Medicine, Cornell University, Ithaca, New York 14853 and the Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208

KLF8 (Krüppel-like factor 8) is a member of the Krüppel transcription factor family that binds CACCC elements in DNA and activates or represses their target genes in a context-dependent manner. Here we present sumoylation as a novel mechanism that regulates KLF8 post-translationally. We found that KLF8 can be covalently modified by small ubiqitin-like modifier (SUMO)-1, SUMO-2, and SUMO-3 in vivo. We showed that KLF8 interacted with the PIAS family of SUMO E3 ligases PIAS1, PIASy, and PIASx but not with E2 SUMO-conjugating enzyme Ubc9. Furthermore, we demonstrated that the E2 and E3 ligases enhanced the sumoylation of KLF8. In addition, site-directed mutagenesis identified lysine 67 as the major sumoylation site on KLF8. Lysine 67 to arginine mutation strongly enhanced activity of KLF8 as a repressor or activator to its physiological target promoters and as an inducer of the G₁ cell cycle progression. Taken together, our results demonstrated that sumoylation of KLF8 negatively regulates its transcriptional activity and cellular functions.

Received for publication, December 8, 2005 , and in revised form, March 23, 2006.

^* This research was supported by Albany Medical College institutional grants and the Wendy Will Case Cancer Fund (to J. Z.) and National Institutes of Health Grants HL73394 and GM52890 (to J.-L. G.). 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: MS338, Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Ave., MC-165, Albany, NY 12208. Tel.: 518-262-2305; Fax: 518-262-5669; E-mail: zhaojh{at}mail.amc.edu.

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