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Molecular and Cellular Biology, December 2003, p. 8528-8541, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8528-8541.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Positive and Negative Regulation of the Cardiovascular Transcription Factor KLF5 by p300 and the Oncogenic Regulator SET through Interaction and Acetylation on the DNA-Binding Domain

Saku Miyamoto,1 Toru Suzuki,1,2,3 Shinsuke Muto,1,3,4 Kenichi Aizawa,1 Akatsuki Kimura,3,4 Yoshiko Mizuno,1 Tomoko Nagino,1 Yasushi Imai,1 Naruhiko Adachi,3,4 Masami Horikoshi,3,4 and Ryozo Nagai1*

Department of Cardiovascular Medicine,1 Department of Clinical Bioinformatics, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655,2 Laboratory of Developmental Biology, Department of Cellular Biology, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032,3 Horikoshi Gene Selector Project, Exploratory Research for Advanced Technology, Japan Science and Technology Corporation, Tsukuba, Ibaraki 300-2635, Japan4

Received 14 May 2003/ Returned for modification 2 July 2003/ Accepted 15 August 2003

Here we show a novel pathway of transcriptional regulation of a DNA-binding transcription factor by coupled interaction and modification (e.g., acetylation) through the DNA-binding domain (DBD). The oncogenic regulator SET was isolated by affinity purification of factors interacting with the DBD of the cardiovascular transcription factor KLF5. SET negatively regulated KLF5 DNA binding, transactivation, and cell-proliferative activities. Down-regulation of the negative regulator SET was seen in response to KLF5-mediated gene activation. The coactivator/acetylase p300, on the other hand, interacted with and acetylated KLF5 DBD, and activated its transcription. Interestingly, SET inhibited KLF5 acetylation, and a nonacetylated mutant of KLF5 showed reduced transcriptional activation and cell growth complementary to the actions of SET. These findings suggest a new pathway for regulation of a DNA-binding transcription factor on the DBD through interaction and coupled acetylation by two opposing regulatory factors of a coactivator/acetylase and a negative cofactor harboring activity to inhibit acetylation.

* Corresponding author. Mailing address for Ryozo Nagai: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5800-6526. Fax: 81-3-3815-2087. E-mail: nagai-tky{at}umin.ac.jp.Mailing address for Toru Suzuki: Department of Clinical Bioinformatics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-3815-5411, ext. 33117. Fax: 81-3-5800-8824. E-mail: torusuzu-tky@umin.ac.jp.

Molecular and Cellular Biology, December 2003, p. 8528-8541, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8528-8541.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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