title: 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.
abstract: 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.
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Saku
authors: S
authors: Miyamoto
authors: Toru
authors: T
authors: Suzuki
authors: Shinsuke
authors: S
authors: Muto
authors: Kenichi
authors: K
authors: Aizawa
authors: Akatsuki
authors: A
authors: Kimura
authors: Yoshiko
authors: Y
authors: Mizuno
authors: Tomoko
authors: T
authors: Nagino
authors: Yasushi
authors: Y
authors: Imai
authors: Naruhiko
authors: N
authors: Adachi
authors: Masami
authors: M
authors: Horikoshi
authors: Ryozo
authors: R
authors: Nagai
mesh_terms: D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D050881:E1A-Associated p300 Protein; D006367:HeLa Cells; D056488:Histone Chaperones; D006801:Humans; D066298:In Vitro Techniques; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C492214:KLF5 protein, human; C118391:Klf5 protein, mouse; C492215:Klf5 protein, rat; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D011506:Proteins; D011994:Recombinant Proteins; C513473:SET protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; C494362:Ep300 protein, rat