Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells

Joongkyu Park,Yohan Oh,Lang Yoo,Min-Su Jung,Woo-Joo Song,Sang-Hun Lee,Hyemyung Seo,Kwang Chul Chung

doi:10.1074/jbc.m110.147520

Abstract

Down syndrome (DS) is associated with many neural defects, including reduced brain size and impaired neuronal proliferation, highly contributing to the mental retardation. Those typical characteristics of DS are closely associated with a specific gene group "Down syndrome critical region" (DSCR) on human chromosome 21. Here we investigated the molecular mechanisms underlying impaired neuronal proliferation in DS and, more specifically, a regulatory role for dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A), a DSCR gene product, in embryonic neuronal cell proliferation. We found that Dyrk1A phosphorylates p53 at Ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor H19-7 cells. In addition, Dyrk1A-induced p53 phosphorylation at Ser-15 led to a robust induction of p53 target genes (e.g. p21(CIP1)) and impaired G(1)/G(0)-S phase transition, resulting in attenuated proliferation of H19-7 cells and human embryonic stem cell-derived neural precursor cells. Moreover, the point mutation of p53-Ser-15 to alanine rescued the inhibitory effect of Dyrk1A on neuronal proliferation. Accordingly, brains from embryonic DYRK1A transgenic mice exhibited elevated levels of Dyrk1A, Ser-15 (mouse Ser-18)-phosphorylated p53, and p21(CIP1) as well as impaired neuronal proliferation. These findings suggest that up-regulation of Dyrk1A contributes to altered neuronal proliferation in DS through specific phosphorylation of p53 at Ser-15 and subsequent p21(CIP1) induction.

Highlights

The typical characteristics of DS are thought to be closely associated with a gene group mapped to a specific region of human chromosome 21q22 “Down syndrome critical region” (DSCR) (3)
Using immortalized rat embryonic hippocampal progenitor H19-7 cells, human embryonic stem cells-derived neural precursor cells, and DYRK1A Tg mice, we provide evidence that Dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A) attenuates neuronal proliferation by direct phosphorylation of p53, an effect that may underlie reduced brain size and neuronal number as well as impaired neuronal proliferation in DS
Dyrk1A Interacts and Co-localizes with p53—We previously observed that ϳ2-fold overexpression of Dyrk1A leads to ADlike neuropathological features, increased susceptibility to serum deprivation-induced apoptosis (14), and growth suppression in H19-7 cells

Summary

Introduction

The typical characteristics of DS are thought to be closely associated with a gene group mapped to a specific region of human chromosome 21q22 “Down syndrome critical region” (DSCR) (3). DYRK1A transgenic (Tg) mice, which express human DYRK1A present on a bacterial artificial chromosome, exhibit significant impairment in hippocampal-dependent memory tasks and altered synaptic plasticity, features that are similar to those seen in DS patients (13). Mice bearing the 152F7 fragment of the yeast artificial chromosome containing DYRK1A gene show learning and memory deficits as well as reduced neuronal density in the cerebral cortex (17). The present study was conducted to investigate the mechanism by which Dyrk1A impairs neuronal proliferation. Using immortalized rat embryonic hippocampal progenitor H19-7 cells, human embryonic stem cells-derived neural precursor cells, and DYRK1A Tg mice, we provide evidence that Dyrk1A attenuates neuronal proliferation by direct phosphorylation of p53, an effect that may underlie reduced brain size and neuronal number as well as impaired neuronal proliferation in DS

Objectives

Results

Conclusion