Dosage of Dyrk1a shifts cells within a p21-cyclin D1 signaling map to control the decision to enter the cell cycle

Mol Cell. 2013 Oct 10;52(1):87-100. doi: 10.1016/j.molcel.2013.09.009.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation*
  • Cell Tracking / methods
  • Chromosomes, Human, Pair 21
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Down Syndrome / genetics
  • Down Syndrome / metabolism
  • Down Syndrome / pathology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • G1 Phase*
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Microscopy, Fluorescence
  • Microscopy, Video
  • Phosphorylation
  • Protein Stability
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • RNA Interference
  • Signal Transduction
  • Time Factors
  • Time-Lapse Imaging
  • Transfection
  • ras Proteins / metabolism

Substances

  • CCND1 protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin D1
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • ras Proteins