Format

Send to

Choose Destination
Cell Cycle. 2014;13(13):2084-100. doi: 10.4161/cc.29104. Epub 2014 May 7.

The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and Cyclin D1 and induces cell cycle exit and neuronal differentiation.

Author information

1
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.
2
Institute of Pharmacology and Toxicology; Medical Faculty; RWTH Aachen University; Aachen, Germany.
3
Instituto de Neurociencias; Consejo Superior de Investigaciones Cientificas (CSIC) and Universidad Miguel Hernandez; Alicante, Spain.

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.

KEYWORDS:

Cyclin D1; DYRK1A; Down syndrome; cell cycle; neuronal differentiation; p27Kip1; phosphorylation

PMID:
24806449
PMCID:
PMC4111700
DOI:
10.4161/cc.29104
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center