title: The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and Cyclin D1 and induces cell cycle exit and neuronal differentiation.
abstract: A fundamental question in neurobiology is how the balance between proliferation and differentiation of neuronal precursors is maintained to ensure that the proper number of brain neurons is generated. Substantial evidence implicates DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A) as a candidate gene responsible for altered neuronal development and brain abnormalities in Down syndrome. Recent findings support the hypothesis that DYRK1A is involved in cell cycle control. Nonetheless, how DYRK1A contributes to neuronal cell cycle regulation and thereby affects neurogenesis remains poorly understood. In the present study we have investigated the mechanisms by which DYRK1A affects cell cycle regulation and neuronal differentiation in a human cell model, mouse neurons, and mouse brain. Dependent on its kinase activity and correlated with the dosage of overexpression, DYRK1A blocked proliferation of SH-SY5Y neuroblastoma cells within 24 h and arrested the cells in G₁ phase. Sustained overexpression of DYRK1A induced G₀ cell cycle exit and neuronal differentiation. Furthermore, we provide evidence that DYRK1A modulated protein stability of cell cycle-regulatory proteins. DYRK1A reduced cellular Cyclin D1 levels by phosphorylation on Thr286, which is known to induce proteasomal degradation. In addition, DYRK1A phosphorylated p27(Kip1) on Ser10, resulting in protein stabilization. Inhibition of DYRK1A kinase activity reduced p27(Kip1) Ser10 phosphorylation in cultured hippocampal neurons and in embryonic mouse brain. In aggregate, these results suggest a novel mechanism by which overexpression of DYRK1A may promote premature neuronal differentiation and contribute to altered brain development in Down syndrome.
authors.affiliation: Institute of Pharmacology and Toxicology; Medical Faculty; RWTH Aachen University; Aachen, Germany; Instituto de Neurociencias; Consejo Superior de Investigaciones Cientificas (CSIC) and Universidad Miguel Hernandez; Alicante, Spain.
authors.forename: Ulf
authors.initials: U
authors.lastname: Soppa
authors.affiliation: Institute of Pharmacology and Toxicology; Medical Faculty; RWTH Aachen University; Aachen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Schumacher
authors.affiliation: Instituto de Neurociencias; Consejo Superior de Investigaciones Cientificas (CSIC) and Universidad Miguel Hernandez; Alicante, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Florencio Ortiz
authors.affiliation: Institute of Pharmacology and Toxicology; Medical Faculty; RWTH Aachen University; Aachen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Pasqualon
authors.affiliation: Instituto de Neurociencias; Consejo Superior de Investigaciones Cientificas (CSIC) and Universidad Miguel Hernandez; Alicante, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Tejedor
authors.affiliation: Institute of Pharmacology and Toxicology; Medical Faculty; RWTH Aachen University; Aachen, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Becker
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D004314:Down Syndrome / Q000378:metabolism*; D006801:Humans; D008813:Mice, Inbred ICR; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012694:Serine; D013912:Threonine; D000097603:Dyrk Kinases
keywords: Cyclin D1; DYRK1A; Down syndrome; cell cycle; neuronal differentiation; p27Kip1; phosphorylation