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

Abstract

Summary 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 co-stabilizing 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.

DYRK1A regulates Hap1–Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome

“…Our data have shown that loss of Hap1 can lead to enhanced interaction between Dcaf7 and DYRK1A, resulting in an increase in DYRK1A. It has been reported that increased DYRK1A can affect cell-cycle regulation and neuronal differentiation by reducing cyclin D1 and the cyclindependent kinase inhibitor p21 (49,50), two important proteins that promote neuronal differentiation (50)(51)(52)(53)(54). Thus, we isolated hypothalamic tissues from WT and Hap1-KO postnatal pups and performed Western blotting with anti-cyclin D1 and anti-p21.…”

DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3

“…This study adds to a growing body of evidence that DYRK1A-and the DYRK family in general (Becker, 2012)-broadly influences cell cycle entry and exit in multiple cell types by phosphorylating both positive and negative cell cycle regulators, including Cyclin D1 (Chen et al, 2013), LIN-52 (Litovchick et al, 2011), p27 (Soppa et al, 2014), and now Cyclin D3. Underscoring its involvement in cell cycle regulation, the human DYRK1A promoter is itself bound and activated by E2F1 (Maenz et al, 2008), but whether this mechanism directs cell cycle exit by phosphorylating T283 on Cyclin D3 to mark the protein for degradation.…”

“…Cyclin D1, although regulated by DYRK1A (Chen et al, 2013;Soppa et al, 2014), is expressed at very low or undetectable levels during lymphoid development (Cooper et al, 2006; Fig. 8 C).…”

“…DYRK1A phosphorylates Cyclin D1 on threonine 286 (T286) to promote its degradation and subsequent cell cycle arrest in developing neurons (Yabut et al, 2010;Soppa et al, 2014) and fibroblasts (Chen et al, 2013). Recent work in our laboratory uncovered a tumor-promoting role for DYRK1A in the megakaryocytic leukemia associated with Down syndrome (Malinge et al, 2012); this was the first report of DYRK1A's importance in a hematopoietic cell type.…”

“…Dual specificity tyrosine-regulated kinase 1A (DYRK1A) has been shown to phosphorylate more than 30 proteins to regulate diverse biological functions, including synaptic transmission (Xie et al, 2012;Chen et al, 2014), neurodegeneration (Wegiel et al, 2011), transcription (Gwack et al, 2006), mRNA splicing (de Graaf et al, 2006), proliferation (Hämmerle et al, 2011;Litovchick et al, 2011;Chen et al, 2013), and survival (Guo et al, 2010;Barallobre et al, 2014). DYRK1A phosphorylates Cyclin D1 on threonine 286 (T286) to promote its degradation and subsequent cell cycle arrest in developing neurons (Yabut et al, 2010;Soppa et al, 2014) and fibroblasts (Chen et al, 2013).…”