title: Dosage of Dyrk1a shifts cells within a p21-cyclin D1 signaling map to control the decision to enter the cell cycle.
abstract: Mammalian cells have a remarkable capacity to compensate for heterozygous gene loss or extra gene copies. One exception is Down syndrome (DS), where a third copy of chromosome 21 mediates neurogenesis defects and lowers the frequency of solid tumors. Here we combine live-cell imaging and single-cell analysis to show that increased dosage of chromosome 21-localized Dyrk1a steeply increases G1 cell cycle duration through direct phosphorylation and degradation of cyclin D1 (CycD1). DS-derived fibroblasts showed analogous cell cycle changes that were reversed by Dyrk1a inhibition. Furthermore, reducing Dyrk1a activity increased CycD1 expression to force a bifurcation, with one subpopulation of cells accelerating proliferation and the other arresting proliferation by costabilizing CycD1 and the CDK inhibitor p21. Thus, dosage of Dyrk1a repositions cells within a p21-CycD1 signaling map, directing each cell to either proliferate or to follow two distinct cell cycle exit pathways characterized by high or low CycD1 and p21 levels.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Jia-Yun
authors.initials: JY
authors.lastname: Chen
authors.forename: Jia-Ren
authors.initials: JR
authors.lastname: Lin
authors.forename: Feng-Chiao
authors.initials: FC
authors.lastname: Tsai
authors.forename: Tobias
authors.initials: T
authors.lastname: Meyer
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058948:Cell Tracking / Q000379:methods; D002891:Chromosomes, Human, Pair 21; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016193:G1 Phase; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D059008:Time-Lapse Imaging; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D019938:Cyclin D1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D018631:ras Proteins; D000097603:Dyrk Kinases; C530104:CCND1 protein, human; C493956:CDKN1A protein, human