title: A KLF4-miRNA-206 autoregulatory feedback loop can promote or inhibit protein translation depending upon cell context.
abstract: Krüppel-like factor 4 (KLF4), a transcription factor that regulates cell fate in a context-dependent fashion, is normally induced upon growth arrest or differentiation. In many cancer cells there is dysregulation, with increased expression in proliferating cells. To identify sequence elements that mediate KLF4 suppression in normal epithelial cells, we utilized a luciferase reporter and RK3E cells, which undergo a proliferation-differentiation switch to form an epithelial sheet. A translational control element (TCE) within the KLF4 3'-untranslated region interacted with microRNAs (miRs) 206 and 344-1 to promote or inhibit KLF4 expression, respectively, in proliferating epithelial cells. Overall, the TCE suppressed expression in proliferating primary human mammary epithelial cells, but this suppressive effect was attenuated in immortalized mammary epithelial MCF10A cells, in which Dicer1 and miR-206 promoted KLF4 expression and TCE reporter activity. In contrast to MCF10A cells, in breast cancer cells the activity of miR-206 was switched, and it repressed KLF4 expression and TCE reporter activity. As miR-206 levels were KLF4 dependent, the results identify a KLF4-miR-206 feedback pathway that oppositely affects protein translation in normal cells and cancer cells. In addition, the results indicate that two distinct miRs can have opposite and competing effects on translation in proliferating cells.
authors.affiliation: Department of Biochemistry, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
authors.forename: Chen-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Liu
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Addison
authors.forename: William F
authors.initials: WF
authors.lastname: Wonderlin
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Ivanov
authors.forename: J Michael
authors.initials: JM
authors.lastname: Ruppert
mesh_terms: D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D016415:Sequence Alignment; D014158:Transcription, Genetic
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C546087:MIRN206 microRNA, human; D035683:MicroRNAs