Dosage of Dyrk1a Shifts Cells within a p21-Cyclin D1 Signaling Map to Control the Decision to Enter the Cell Cycle

• Published in: Molecular cell Vol. 52; no. 1; pp. 87 - 100
• Main Authors: Chen, Jia-Yun, Lin, Jia-Ren, Tsai, Feng-Chiao, Meyer, Tobias
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2013
• Subjects: cell cycle; Cell Line, Tumor; Cell Proliferation; Cell Tracking - methods; cells; chromosomes; Chromosomes, Human, Pair 21; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; cyclins; Down syndrome; Down Syndrome - genetics; Down Syndrome - metabolism; Down Syndrome - pathology; Dyrk Kinases; fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; G1 Phase; gene deletion; Gene Expression Regulation; Gene Knockdown Techniques; genes; heterozygosity; Humans; image analysis; mammals; Microscopy, Fluorescence; Microscopy, Video; neoplasms; neurogenesis; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein Stability; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; ras Proteins - metabolism; RNA Interference; Signal Transduction; Time Factors; Time-Lapse Imaging; Transfection
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2013.09.009

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. [Display omitted] •Increased Dyrk1a dosage steeply increases the duration and variability of G1 phase•A p21-cyclin D1 signaling map specifies cell cycle entry and exit decisions•Dosage of Dyrk1a controls the relative cyclin D1 and p21 protein levels•Extra-dosage of Dyrk1a explains the cell cycle changes in Down syndrome cells