title: GSK3β-dependent phosphorylation alters DNA binding, transactivity and half-life of the transcription factor USF2.
abstract: The upstream stimulatory factor 2 (USF2) is a regulator of important cellular processes and is supposed to have also a role during tumor development. However, the knowledge about the mechanisms that control the function of USF2 is limited. The data of the current study show that USF2 function is regulated by phosphorylation and identified GSK3β as an USF2-phosphorylating kinase. The phosphorylation sites within USF2 could be mapped to serine 155 and threonine 230. In silico analyses of the 3-dimensional structure revealed that phosphorylation of USF2 by GSK3β converts it to a more open conformation which may influence transactivity, DNA binding and target gene expression. Indeed, experiments with GSK-3β-deficient cells revealed that USF2 transactivity, DNA binding and target gene expression were reduced upon lack of GSK3β. Further, experiments with USF2 variants mimicking GSK3β phosphorylated USF2 in GSK3β-deficient cells showed that phosphorylation of USF2 by GSK3β did not affect cell proliferation but increased cell migration. Together, this study reports a new mechanism by which USF2 may contribute to cancerogenesis.
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Chemistry, University of Kaiserslautern, Kaiserslautern, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Horbach
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Tabughang Franklin
authors.initials: TF
authors.lastname: Chi
authors.affiliation: Medical Biochemistry and Molecular Biology, Saarland University, Homburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Götz
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Satyan
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: André H
authors.initials: AH
authors.lastname: Juffer
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Elitsa Y
authors.initials: EY
authors.lastname: Dimova
authors.affiliation: Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kietzmann
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006207:Half-Life; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D010766:Phosphorylation; D015533:Transcriptional Activation; D051720:Upstream Stimulatory Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
chemical_list: C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3