title: Cooperative transcriptional activation by Klf4, Meis2, and Pbx1.
abstract: The Kruppel-like factor Klf4 is implicated in tumorigenesis and maintaining stem cell pluripotency, and Klf4 can both activate and repress gene expression. We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or GC box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. In HepG2 cells, reducing expression of endogenous Meis2 or Pbx1 decreases p15 gene expression and increases the number of cells entering S phase. Although DNA binding by all three proteins contributes to full cooperative activation, the sequence requirements for binding by Meis2 and Pbx1 are variable. In the E-cadherin promoter, a Pbx-like site is required for full activation, whereas in the p15 promoter, the Klf4 site appears to play the major role. Through a bioinformatics search we identified additional genes with conserved binding sites for Klf4, Meis2, and Pbx1 and show that at least some of these genes can be activated cooperatively by Klf4 and Meis2/Pbx1. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. This provides a mechanism to modulate transcriptional regulation by the multifunctional Klf4 transcription factor.
authors: Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908, USA.
authors: Glen A
authors: GA
authors: Bjerke
authors: Cathy
authors: C
authors: Hyman-Walsh
authors: David
authors: D
authors: Wotton
mesh_terms: D000818:Animals; D001482:Base Composition; D019556:COS Cells; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis* / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006367:HeLa Cells; D056945:Hep G2 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D015820:Cadherins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C491172:MEIS2 protein, human; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C083400:PBX1 protein, human; D004247:DNA