title: A small ubiquitin-related modifier-interacting motif functions as the transcriptional activation domain of Krüppel-like factor 4.
abstract: The zinc finger transcription factor, Krüppel-like factor 4 (KLF4), regulates numerous biological processes, including proliferation, differentiation, and embryonic stem cell self-renewal. Although the DNA sequence to which KLF4 binds is established, the mechanism by which KLF4 controls transcription is not well defined. Small ubiquitin-related modifier (SUMO) is an important regulator of transcription. Here we show that KLF4 is both SUMOylated at a single lysine residue and physically interacts with SUMO-1 in a region that matches an acidic and hydrophobic residue-rich SUMO-interacting motif (SIM) consensus. The SIM in KLF4 is required for transactivation of target promoters in a SUMO-1-dependent manner. Mutation of either the acidic or hydrophobic residues in the SIM significantly impairs the ability of KLF4 to interact with SUMO-1, activate transcription, and inhibit cell proliferation. Our study provides direct evidence that SIM in KLF4 functions as a transcriptional activation domain. A survey of transcription factor sequences reveals that established transactivation domains of many transcription factors contain sequences highly related to SIM. These results, therefore, illustrate a novel mechanism by which SUMO interaction modulates the activity of transcription factors.
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: James X
authors.initials: JX
authors.lastname: Du
authors.forename: Beth B
authors.initials: BB
authors.lastname: McConnell
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Yang
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D055785:Gene Knockdown Techniques; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D008239:Lysine; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D025842:SUMO-1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D025842:SUMO-1 Protein; D008239:Lysine